text:
By DAVID SMITH JR.
Special to The Hays Daily News
Park City, Kansas - June 24, 2014 - Sprint car action gets back underway this coming weekend as the National Championship Racing Association of Park City, Kansas presented by Precise Racing Products sprint car division takes part in a weekend double header this Saturday and Sunday night, June 28-29 at two different racing venues in the state of Kansas. Both events will be co-sanctioned with the American Bank of Oklahoma American Sprint Car Series Sooner Region.
It all kicks off on Saturday night as both series head to Dodge City Raceway Park in Dodge City, Kansas for the Sixth annual Steve King Memorial. The NCRA 360-ci sprint car tour last visited the west Kansas facility back in 2012 when it was Logan Forler who picked up the victory, his first career with the series. In fact, nine different drivers have reached victory lane at the track since 2006. Among them include Forler, Ryan Roberts, J.D. Johnson, Jason Martin, Mike Peters, Koby Barksdale, Don Droud, Jr., Garry Lee Maier and Gary Wright.
Both series then move east to 81 Speedway in Park City for a Sunday night showdown billed as the "Harvest of Gold Challenge." to wrap up the weekend and all events will pay the standard $2000 to win, $300 to start purse.
Thus far during the 2014 race season, four different drivers have reached victory lane with two of those drivers earning their first career series victories. Jack Dover of Springfield, Nebraska won the last completed event held at 81 Speedway during the annual running of the "Hoosier Daddy" Father's Day Spectacular. Longdale Speedway in Longdale, Oklahoma recently held their first ever NCRA sprint car event and it was Jeff Stasa earning his first career sprint car victory. Dover picked up the checkered flag in the series first ever appearance at Butler County Speedway in Rising City, Nebraska with Danny Wood claiming honors at the Kansas State Fairgrounds in Hutchinson, Kansas back in April. Kevin Swindell took home the victory and $5000 in the season opener at 81 Speedway during the fourth annual "Air Capital Shootout."
Former tour champion Jeremy Campbell of Wichita holds a 30 point lead over defending tour champion C.J. Johnson of Quinter, Kansas. J.D. Johnson sits third in the standings, followed by Danny Wood and Jon Freeman. Rounding out the top ten in the point standings are; Stasa, Luke Cranston, Raymond Seeman, Jake Greider and Kris Miller. Other drivers expected include Jordan Weaver, Michelle Decker, Wyatt Burks, Jake Martens and Zach Blurton. Greider also leads Seeman in the tours rookie of the year honors.
The ASCS Sooner Region is led by their current point leader Dustin Morgan. Drivers representing the series expected to be on hand this weekend include; Alex Sewell, Mike Goodman, Harli White, Sean McClelland, Kyle Chady, Zach Pringle and Robert Sellers.
Tickets for Saturday's Sixth Annual Steve King Memorial in Dodge City are just $20 with children 11 and under free when accompanied by an adult. Pit passes are $30.
Dodge City Raceway Park is located on the south edge of Dodge City, KS, on US 283, then 0.9 miles west on US 56, then 0.1 miles south. For more information, contact the track at 620-225-3277 or check www.dodgecityraceway.com.
General admission tickets for Sunday nights "Harvest of Gold Challenge" at 81 Speedway are just $15.00 for adults ages 11 and up and $5.00 for children 6 thru 10.
81 Speedway is located north of Wichita on I-135 to exit 16, then .7 mile west on 77th St. in Park City. For more race information contact the 81 Speedway office (316) 755-1781.
For more information on the 25th anniversary season for the NCRA 360-ci sprint car series contact the office (316) 755-1781. To view current point standings, 2014 schedule and more log on to www.racencra.com.
The HDNews.net/racing Channel is available on YouTube, featuring in-car camera videos and much more.


text:
Root Catalog
Shop by Brand
Filtex 12 Gallon Central Vacuum Cleaner Micro-lined Bags, 4 Pack.
$12.95These are 4 generic Filtex central vacum cleaner bags made by DVC. Each bag is approximately 12 gallons in capacity. Fits Original Filtex part number 12G. Filtex models that use this bag include; TC600L, TM285L, TS300L, TSP300L, S300, SP700, 400, 500, 500 Learn More -
Numatic HEPA-Flo Canister Vacuum Cleaner Bags, NVM-2BH Part Number 604016. 10 Bags Per Pack.
$34.99These are genuine Numatic HEPA-Flo canister vacuum cleaner bags for the Numatic Henry model HVR-200M and James model JVH-180. Each bag has it's own seal, so when the it's time to replace the bag, you may easily seal the bag first before removing it, preven Learn More -
N.A.C.E. & Numatic Henry and James NVM 1C/2 10 Pack Generic Vacuum bags
$21.95N.A.C.E. & Numatic Henry and James NVM 1C/2 10 Pack Generic Vacuum bags use the highest quality Micro-Plus filter Learn More -
Numatic Henry HEPA Flo Bags NVM1Ch (10pk)
$23.95Nacecare Numatic Henry Hepa Flo filter bags for 130/180/200 models, Hepa H11 NVM1CH (604015) 10 Pack Generic Vacuum bags. Learn More -
Nacecare Numatic BackPack RSV130 10 Pack Generic Vacuum bags
$19.95Nacecare Numatic BackPack RSV130 10 Pack Generic Vacuum bags use the highest quality Micro-Plus filter media Learn More -
Nacecare Numatic Charles & George Bag NVM2B/2 10 Pack Generic Vacuum bags
$19.95Nacecare Numatic Charles & George Bag NVM2B/2 10 Pack Generic Vacuum bags use the highest quality Micro-Plus filter media Learn More -
Numatic CVC-370 Charles Canister Vacuum Cleaner
$399.99Numatic Charles CVC370 Canister Vacuum. The Charles CVC-370 Vacuum Cleaner Has Video Reviews At GoVacuum, Where Charles Cvc370 Ships At No Cost! Learn More -
Numatic George GVE-370 Vacuum
$599.00George Accessory Kit A26A Contents 1.9m Nuflex Bayonet Hose 300mm Combination Floor Nozzle 240mm Crevice Tool Tritex Filter Learn More -
Numatic Henry Micro HVR-200M Vacuum
$449.00Henry Accessory Kit JV1 Contents 1.9m Nuflex Bayonet Hose 300mm Combination Floor Nozzle Aluminium Extension Tube 240mm Crevice Tool Learn More -
Numatic Nacecare James JVP-180 Commercial Canister Vacuum Cleaner
$399.00Small dry vac with powerful 1100W motor; unique 'caddy' top allowing storage of small tools, duster, polish, etc., also cable when not in use. Learn More -
Nacecare HVR200A Numatic Henry GoVacuum Pet Edition
$499.95The Numatic Henry HVR 200A GoVacuum Pet Edition has a TurboCat & A 10 Year Warranty! The Henry HVR200A GoVacuum Pet Edition Has A Video Review and a 60 day in home trial. Learn More -
Numatic ProVac PVR 390 Commerical Dry Vac Cleaner - Just Like New
$449.00The ProVac range is a perfect example of combining the very best innovation into a single product range to produce exceptional results in many more ways than one could imagine. Learn More -
Numatic HET200A Hetty HEPA Canister Vacuum Cleaner
$389.00HET200A Kit A1 Order codes 820916 HET200A Hetty 240V + Kit A1 Hetty (short for Henrietta) is not just a pretty face, she has all the Henry features and specification: giant TwinFlo', long life, 2-stage motors; with AutoSave - Energy Conservation - 50% Ene Learn More -
Numatic Hi-Power Canister Vacuum Cleaner with Accessory Tool Kit, JVP180-1,"James" (Color: Yellow)
$269.00Numatic James classic Vaccum Cleaner with Accessory Tool Kit, JVP180-1 (Color: Yellow). Your top-performing vaccum cleaner with a personality... It features handy storage in the Head; large color coated wheels, a stainless steel base plate, and cable stor Learn More -
Mini Blind Brush
$14.95Mini Blind Brush. Free Shipping if ordered with any vacuum you buy.Removes Dust Fast and Effectively Attaches Easily to your Vacuum Cleaner's Hose Extremely Lightweight Mini blind window coverings are a very popular choice when it comes to home interior d Learn More -
Central Vacuum Hose Hanger
$10.99Central Vacuum Hose Hanger for CVAC hoses. Strong Reinforced hose Hanger made of Plastic. Easy to Install Central Vacuum Reinforced Hose Hanger. Learn More

subset: commoncrawl


text:
If anyone alive could bring legitimacy to the sound of your average nightclub, it's progressive house mainstay Paul Van Dyk. Though the German... More >>
Considering the uneven and, occasionally, unintentionally hilarious results of conceptualism, one should expect Matmos to choke on flatulent gusts... More >>
It's barely a minute into Mogwai's fourth LP before we get a breathtaking glimpse of all that makes the group stand out from its postrock... More >>
The Belgian-born Natacha Atlas has been impressing the rest of the world since the mid-Eighties. Her forlorn, aching vocals on solo LPs like... More >>
Ever since Björk and Beth Orton made it safe for female singer-songwriters to explore electronica, an aural land-grab of sorts has now ensued... More >>
Once an electronica act has established an international career, things can get a bit dull if one doesn't take some chances every now and again.... More >>


text: GALLERIES Mitch Glazer Peter Bogdanovich Peter Bogdanovich T.I. T.I. Mike White Mike White Ice-T Ice-T Coming Next OR 0 9 Back to Top ▲ Mitch Glazer Mitch Glazer Mitch Glazer Pictures AskMen Editors Share on Facebook Share on Twitter 0 Shares Next Page Comments Show Comments More Like This Promoted Around the Web Special Features


text:
- The Orlando Magic's defense is in for a challenge against the Oklahoma City Thunder — owners of the league's most efficient offense.
- John Denton of OrlandoMagic.com: "The Magic (18-47) will face the ultimate road challenge tonight when the play the Oklahoma City Thunder (48-17) at noisy Chesapeake Energy Arena. The Thunder have been especially good playing in front of their boisterous crowd, going 29-4 at home this season. To put into perspective just how much of a difference the home atmosphere means to the Thunder, they are just 19-13 on the road this season."
- Were Magic fans right to boo Dwight Howard on Tuesday? According to Andrew Unterberger of The Basketball Jones, they were.
- Adi Joseph of USA TODAY Sports predicts the Magic-Thunder game will be a blowout.
- Matt Dollinger of Sports Illustrated compares Orlando's season to The Hangover: "You had to expect this type of year after the Magic gave into Dwight Howard's trade demands. Orlando has at least seen strong play from some of the pieces acquired in that deal — Arron Afflalo and Nikola Vucevic — but there are only two cures for this type of hangover: cap room and lottery picks. Luckily for Orlando, it's assembling the pieces needed to shake this one off."
Mar 15


text:
As sister Kim is starting to gain baby weight, Kourtney has shed all of the weight she gained from second child Penelope — almost 50 pounds in just 6 months! Find out how she did it below!
On the heels of Kim Kardashian's pregnancy annoucement, Kourtney Kardashian is spilling the diet secrets that allowed her to shed all of the weight she gained while pregnant with daughter Penelope Scotland Disick. You'll never believe what's on her diet — cookies! Keep reading to see how she lost so much weight so fast!
Kourtney admitted to Us Weekly that after she gave birth to her son Mason in 2009, she went on an unhealthy crash diet.
"I was comparing myself to other people and putting all this pressure on myself. I was working out and I wasn't eating enough. I definitely pushed myself too hard."
After she had her daughter Penelope on July 8, 2012, Kourtney knew she had to lose the weight the healthy way.
Kourtney follows pro trainer Tracy Anderson's 90-minute dance-focused workout. In just 6 months, she lost the 45 pounds of weight she gained during her second pregnancy and is down to just 106 pounds! Here are some of her secrets:
How She Lost The Weight
Walking — "I did tons of walking with this massive stroller I have called the Bugaboo Donkey. It holds two kids, so I would put them both in and go for an hourlong walk. A lot of it would be uphill, so it would be pretty major."
Training With Tracy — "We've been doing it for about a month and it has totally changed the shape of my body. The trainer comes over at 7 in the morning when my kids are still asleep so I don't have any mom guilt."
Using Kim As A Workout Buddy — "There are times when I'd say, 'I'll walke up at 9 when everyone else is getting up.' But she'd be like, 'We're working out.' If one of us isn't in the mood, we push each other. I think we motivate each other to eat well too."
Her Diet Tips & Tricks
Having An Occasional Splurge — "Yesterday my cousin sent us there buttery Armenian cookies called simit and Kim and I finished the entire bag! You can't be trapped by some kind of strict diet plan. You need to live."
Everything In Moderation — "I don't count calories. I just try not to overeat and I keep portions down. My breakfast every day is a protein shake with a banana, an apple, nonfat yogurt, milk, almonds, cinnamon and ice with a scoop of vanilla QuickTrim. For lunch I'll have a piece of fish or a salad with avocado. And then for dinner I'll make fresh soup in my blender, like butternut squash or tomato and zucchini."
Tricks Of The Trade — "I cut up celery and put it in bags to take with a little bit of hummus." She also drinks lots of green tea.
Cutting Out Alcohol — "I don't drink because I'm breast-feeding. Besides, drinking doesn't fit into my lifestyles of walking up super early and working out."
Motivation From Her Man — [Scott Disick likes my curves] he does. He likes me anyway. But I think his favorite is when I'm skinnier."
Will you use some of Kourtney's post-baby weight loss tips, HollyMoms?
– Dory Larrabee
More Kardashian News:
- Kim Kardashian: Being Pregnant Is 'Painful'
- Jessica Alba & Kourtney Kardashian: Stay-Slim Secrets Revealed
- Kourtney Kardashian Shows Off Baby Penelope — Gorgeous New Pics
View Comment
Posted at 9:51 AM on March 31, 2013
Be realistic in your weight-loss goals. Healthy weight loss is 1-2 pounds per week. This may not seem like very much, but it will allow your body to adjust to its new shape. Losing weight too quickly can slow down your metabolism, making it harder for you to reach your ultimate goal.
Posted at 10:37 PM on January 9, 2013
joanne cutebabe
Posted at 1:11 AM on January 9, 2013
Posted at 10:51 AM on January 8, 2013
Posted at 4:18 AM on January 27, 2013
Posted at 9:24 PM on February 3, 2013
Posted at 8:15 PM on January 3, 2013
She looks stunning, always has done even when she's pregnant. She carries herself extremely well, and she can comfortably afford to spend thousands of pounds of personal trainers and things like that if she wishes. So why shouldn't she?
She is a wonderful young woman, however In my opinion she dresses her son more like a girl, although it's her son and as long as he looks perfect to her no one else opinion really matters.
Posted at 8:24 PM on January 2, 2013
Posted at 8:13 PM on January 2, 2013
It is not easy to lose weight after the baby is born. A simple trip to the gym requires a sitter or other newborn child care. The first few months are ones of sleep deprivation. It is tough to go work out when all you really want is an hour of sleep. Cutting back on portion size helps, but without the workout, it is a tough, long road to a 40 or 50 lb weight loss.
Posted at 4:49 PM on January 2, 2013


text:
- Age / Gender:
- 24, Male
- Location:
- Dearborn, MI
- Joined:
- 4/22/06
- All Stats >
I really enjoy web hacking, programming, going to local shows, and watching horror movies.
User Statshot
- Community Stats
Level 4 Blank Slate
Normal Whistle
Ranked as Civilian
Contact Info / Websites
Recent Game Medals
Conquer Africa
5 Points
Zombie Pharaohs? Hasn't that been done before?
Medal Stats.
Fully Upgrade One Item
5 Points
Fully upgrade the quality of one item in your sales department.
Medal Stats.
Conquer the South Pole
5 Points
Penguin zombies are no joke.
Medal Stats.
Conquer the North Pole
5 Points
Zombify Santa.
Medal Stats.
10 Points
Play 9 songs
Medal Stats.
True Listener
25 Points
Finish all songs
Medal Stats.
25 Points
hit 1600 perfect notes
Medal Stats.
10 Points
Unlock 17 stars
Medal Stats.
Wow Particles
5 Points
Finish the fifth song
Medal Stats.
100 Points
Be ranked in the top 89% overall score
Medal Stats.
Total Medals Earned: 32 (From 3 different games.)


text:
Joel W. Goldwein, MD
OncoLink Founder
Ultima Vez Modificado: 20 de mayo del 2000
Presenter: M. Benasso
Affiliation: Inst Nazionale per la Ricera sul Cancro and affiliated centers, Genoa, Italy
It has previously been shown that alternating chemo-radiotherapy (ALT) has improved outcome compared with conventional RT in advanced-stage Squamous cell carcinoma of the head and neck. This study compared the alternating chemo-RT regimen with a partly accelerated radiotherapy (PA-RT) regimen without chemotherapy in a similar patient population.
Materials and Methods:
Authors' Conclusions
Clinical/Scientific Implications:
Apr 15, 2010 - Accelerated fractionation of radiotherapy is an effective alternative to conventional fractionation for squamous-cell carcinoma of the head and neck in developing countries, according to research published online April 9 in The Lancet Oncology.


text:
Long time legislator Merle Phillips dead at 85
SUNBURY – Former state representative in the 108th legislative district, Merle Phillips, has died at the age of 85. Phillips died Monday morning surrounded by his family. State Representative Lynda Schlegel Culver spent decades working closely with Phillips and eventually succeeded him in his post when he decided to retire.
Culver said, "I think the message I walked away with is Merle believed in giving everyone a first, a second and a third chance. He believed everybody made mistakes, everybody deserves forgiveness and if we could help somebody, it was our job to do that."
On the personal side, Culver said, "He had a wicked sense of humor. Most people thought he was always so serious, but he definitely had a wicked sense of humor. He was just a true gentleman and a really remarkable man."
Phillips served the 108th district from 1980 until 2010. He was also appointed as a Northumberland County Commissioner in 2010 to finish the term of State Representative Kurt Masser. Prior to his election to the State House, Phillips was the president of Irish Valley Food Processing. He also served in the United States Marine Corps for four years of active duty and two years in the reserves. He was married and had five children. Funeral arrangements have not yet been announced. (Ali Stevens)
Powered by Facebook Comments


text:
Tuesday, June 2, 2009 at 7:46 AM
Ohio will lose three plants in the bankruptcy and restructuring of General Motors.
Tuesday, June 2, 2009 at 1:41 AM
Ohio dodges a bullet in the GM bankruptcy plant closings.
Monday, June 1, 2009 at 5:06 PM
General Motors Corp says it will close 14 plants as part of it's massive bankruptcy filing - three in Ohio.
Monday, June 1, 2009 at 4:55 PM
There were sighs of relief in Parma, where GM operates a powertrain unit and a stamping plant. Most operations there will continue.
Monday, June 1, 2009 at 8:07 AM
The University Of Cincinnati is offering its own stimulus package for professionals who've been disadvantaged by the economic slump.
Monday, June 1, 2009 at 8:00 AM
If Governor Ted Strickland and lawmakers go to the rainy day fund to plug a $900 million deficit in the state budget, it could create more problems.
Monday, June 1, 2009 at 5:14 AM
Former Ohio Congressman John Kasich later today will formally announce his bid to challenge Democratic Governor Ted Strickland governor in 2010.


text:
Thule Hyper XL 612 The Hyper Box offers luxurious space with outstanding quality, security and ultra-conveniences. $959.95 Read more
Thule Sonic The Sonic Box combines efficiency with style. Swatch silver glossy Swatch black glossy From $549.95 View products
Thule Interstate 869 Thule's most weather-resistant cargo bag ever is large enough to haul your family's vacation gear and durable enough to last over time. $199.95 Read more
Thule Outbound 868 The perfect travel companion, the Outbound installs quickly and easily, packs a full load of gear, and compacts down for smart storage until the next adventure. $99.95 Read more
Thule Canyon 859 The Thule Canyon roof basket gives you additional storage space while still allowing gear to be easily accessible. With its robust, tubular steel design, it is ideal for hauling gear of all shapes and sizes. $299.95 Read more
Thule Transporter 665C Full featured hitch cargo box with tilt down design allows for partial access to trunk, hatch or tailgate. $559.95 Read more


text:
- About this Journal ·
- Abstracting and Indexing ·
- Advance Access ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Articles in Press ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
BioMed Research International
Volume 2013 (2013), Article ID 946206, 12 pages
Emerging Metabolic Targets in the Therapy of Hematological Malignancies
University of Bern, Department of Clinical Research, Division of Pediatric Hematology/Oncology, Murtenstrasse 31, 3010 Bern, Switzerland
Received 24 April 2013; Revised 15 July 2013; Accepted 15 July 2013
Academic Editor: Beric Henderson
Copyright © 2013 Zaira Leni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
During the last decade, the development of anticancer therapies has focused on targeting neoplastic-related metabolism. Cancer cells display a variety of changes in their metabolism, which enable them to satisfy the high bioenergetic and biosynthetic demands for rapid cell division. One of the crucial alterations is referred to as the "Warburg effect", which involves a metabolic shift from oxidative phosphorylation towards the less efficient glycolysis, independent of the presence of oxygen. Although there are many examples of solid tumors having altered metabolism with high rates of glucose uptake and glycolysis, it was only recently reported that this phenomenon occurs in hematological malignancies. This review presents evidence that targeting the glycolytic pathway at different levels in hematological malignancies can inhibit cancer cell proliferation by restoring normal metabolic conditions. However, to achieve cancer regression, high concentrations of glycolytic inhibitors are used due to limited solubility and biodistribution, which may result in toxicity. Besides using these inhibitors as monotherapies, combinatorial approaches using standard chemotherapeutic agents could display enhanced efficacy at eradicating malignant cells. The identification of the metabolic enzymes critical for hematological cancer cell proliferation and survival appears to be an interesting new approach for the targeted therapy of hematological malignancies.
1. Introduction
This paper will review a variety of important aspects of metabolic processes relevant to cancer development and maintenance, with a focus on haematological malignancies (HMs). In addition, we will highlight small molecule compounds that inhibit glycolysis and other interconnected processes and their potential applications in HMs treatment.
Over the past decades, many research groups have commonly reported that one of the main features of tumor cells is to bear a variety of mutations that combine to redirect the network of intracellular signalling pathways. Moreover, modern high-throughput DNA sequence analysis has suggested that these mutations are more numerous and heterogeneous than previously thought [1, 2]. In some cases, the mutations differ among histopathologically identical tumors and are altered during the process of tumor progression [3]. As a consequence, tumor development and progression are increasingly considered to be extremely complex processes. Thus, in most cases, it will be difficult or impossible to specifically eradicate cancer cells by targeting a single oncogene. Hence, further insights into the biological differences between cancer cells and normal cells are necessary to design and develop novel selective and effective anticancer therapies. However, it is becoming extensively clear that many oncogene-activated signalling pathways converge towards an adaptation of tumor cell metabolism to provide energy and essential biomolecules required for the rapid cell division [4–6]. Within the last years, a large variety of different solid tumors have been associated with increased metabolism (i.e., prostate cancer [7], breast cancer [8], glioblastoma [9], ovarian carcinoma [10], pancreatic cancer [11], and many others). It is now accepted that the metabolism of cancer cells has extremely unique characteristics compared to the one of healthy nonproliferating cells [4]. Indeed, cancer cells display a metabolic adaptation called aerobic glycolysis or "Warburg effect", which consists of a metabolic shift to increase the glycolytic pathway as a main source of ATP, instead of oxidative phosphorylation (OXPHOS), independent of the presence of oxygen [12, 13]. Several studies have demonstrated that this shift massively contributes to satisfying the high bioenergetic and biosynthetic demands for rapid cell division in cancers [12–14]. In addition, high rates of glycolysis in tumor cells have been related to resistance to chemo- and radiotherapy treatment [15]. These observations suggest that blocking glycolysis may negatively affect tumor progression and may enhance the efficacy of chemo- and radiotherapy. Indeed, a variety of studies performed in vivo (i.e., human osteosarcoma, lung carcinoma [15], and ovarian cancer [16]) and in vitro (i.e., glioma, squamous carcinomas, and colon carcinoma cells [17]) have revealed that targeting the glycolytic pathway with specific compounds increases the cellular sensitivity toward commonly used anticancer drugs.
2. Glycolysis
Glycolysis is a 10-step pathway that converts a glucose molecule into 2 pyruvates with a net production of 2 ATP molecules and in parallel provides intermediates for anabolic pathways (Figure 1). Each step of the glycolytic reaction is catalyzed by a specific enzyme or enzyme complex. Some of these enzymes comprise isoform variants that are expressed in a context- and tissue-dependent manner [18], leading to enhanced complexity in the glycolytic pathway. Different glycolytic proteins have been reported to be deregulated in various cancers, thus contributing to aerobic glycolysis (Table 1).
3. Glucose Transporters
The entry of glucose into cells is achieved via facilitated diffusion through the glucose transporters (GLUT) family [18]. This family consists of 14 proteins grouped in 3 subclasses, which differ from one another in their affinity for glucose [19]. GLUT1 promotes elevated rates of glucose transport into cells, and the deregulation of its expression has been reported in many tumours, but not in normal tissues [20].
4. Hexokinase
Hexokinase (HK) comprises four isoforms (I to IV), which differ in their kinetics proprties, as well as in their tissue-specific expression and subcellular localization [21, 22]. The hexokinase isoform II (HKII) is known to play a crucial role in initiating and maintaining the high glucose catabolic rates of rapidly growing tumors [23, 24]. Certain tumor cells display an increased gene copy number in HKII [25]. The HKII gene promoter is the target of multiple signals activated by glucose, hypoxic conditions, and insulin, all of which enhance the rate of its transcription [26, 27]. Due to the binding of HKII to the mitochondrial outer membrane where the voltage-dependent anion channel (VDAC) is located [22], this enzyme uses the ATP produced by oxidative phosphorylation as a substrate to produce G-6-P. This interaction of HKII with the mitochondrial membrane appears to be tighter in tumor cells than in normal cells [28]. The HKII-VDAC interaction is thought to be the link between altered cellular metabolism and inhibition of apoptosis because it confers resistance against mitochondrial membrane permeabilization, which is a critical step in apoptosis [29].
5. Glucose-6-Phosphate Isomerase
The third glycolytic enzyme in the pathway is glucose-6-phosphate isomerase (PGI). This enzyme is used as a prognostic marker, as the expression of PGI is associated with cancer progression and an aggressive malignant behavior [30, 31]. However, the involvement of PGI in cancer metabolism has not been completely elucidated yet.
6. Phosphofructokinase
The following enzyme in the pathway is phosphofructokinase (PFK), which is an important control point in the glycolytic pathway and is generally thought to maintain the glycolytic flux [32, 33]. PFK activity is markedly increased in cancer cell lines and primary tumor tissues in situ [34–36]. Elevated PFK-1 activity is also characteristic of cancer cells and is induced in response to oncogenes or following hypoxia-inducible factor 1α (HIF1α) activation [21, 37]. It has been recently reported that the inhibition of PFK by posttranslational modification, such as glycosylation, confers a selective growth advantage to cancer cells [38].
7. Glyceraldehyde-3-Phosphate Dehydrogenase
Another enzyme associated with increased glycolytic activity is glyceraldehyde-3-phosphate dehydrogenase (GAPDH) [39, 40]. GAPDH affects multiple cellular processes including endocytosis, exocytosis, membrane fusion, vesicular secretory, neuronal apoptosis, DNA replication and repair, nuclear tRNA transport, and cytoskeletal organization [21, 41], due to its known nonenzymatic activities, such as binding to NAD+ or NADH and also to DNA and RNA [35, 42–44].
8. Pyruvate Kinase
The final reaction of glycolysis is catalyzed by pyruvate kinase (PK), which has been reported to play a crucial role in reprogramming glycolytic metabolism. There are four mammalian PK isoenzymes (M1, M2, liver isoform (L), and a red blood cell isoform (R)). PKM2 is the embryonic and cancer-associated isoform and exerts its function by forming a tetramer or a less active dimer [45]. The less active dimeric form of PKM2 is mainly found in cancer. It is most commonly expressed in colon cancer [46], renal carcinoma [47], breast cancer [48], lung cancer, and gastrointestinal tumors [49]. PKM2 is known to directly contribute to the Warburg effect [46], as it contributes to the accumulation of glycolytic intermediates for the following anabolic processes: nucleic acid, amino acid, and phospholipid synthesis [50]. PKM2 imparts a growth advantage to tumor cells, particularly under hypoxic conditions. Replacement of PKM2 by the normal adult isoform PKM1 in tumor cells decreased their glycolytic rate and diminished their ability to grow as xenografts [46].
9. Lactate Dehydrogenase
Lactate dehydrogenase (LDH) is a tetrameric enzyme that exists in five isoforms, mostly located in the cytosol [51]. The five isoforms are made up of various possible combinations of the two types of subunits: LDH-A and LDH-B [52]. It has long been appreciated that many human cancers have higher levels of LDH expression than normal tissue [53, 54], and, therefore, LDH has already been acknowledged as one of the most promising cancer targets. In fact, the inhibition of LDH-A had an antiproliferative effect on breast tumor [55, 56]. In addition, studies in primary lymphoma of the breast suggest that aggressive behavior and elevated LDH levels are prognostic factors for poor prognosis and survival [57].
10. Tricarboxylic Acid Cycle
Mitochondrial pyruvate dehydrogenase (PDH) converts pyruvate into acetyl-CoA, which is further directed into the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation. PDH is negatively regulated by pyruvate dehydrogenase kinase (PDK) via phosphorylation [58]. This phosphorylation of PDH decreases the entry of pyruvate into the mitochondrial oxidative metabolism [59]. PDK is known to be a key regulator of the Warburg effect [60] and considered as a novel therapeutic target in oncology [61].
A broad range of cancer types appear to have an increased glycolytic pathway and to take advantage of using intermediates for anabolic reactions [62, 63]. Transcription factors such as HIF1α [64, 65], c-Myc [66–68], and p53 [69] contribute directly or indirectly to this metabolic adaptation of tumors. These interactions seem to be fundamental to direct the aberrant metabolic behavior of tumor cells by promoting the Warburg effect [67–70]. Nevertheless, the gene networks involved in cancer metabolism have not been completely elucidated yet. Thus, it would be beneficial to reverse the Warburg effect in order to normalize tumor metabolism, which may be a potential therapeutic strategy for the treatment of cancer.
Since one feature of HMs is their potential for rapid proliferation and high metabolic demand, a better understanding of the regulation of the multiple metabolic pathways in HMs may reveal new therapeutic opportunities, particularly by restoring the altered cancer energy metabolism.
11. Preclinical Efficacy of Glycolytic Inhibitors
Glycolysis inhibitors have been usually developed to target enzymes that are deregulated in cancer cells compared to their normal counterparts. Many glycolytic inhibitors have been developed so far, and their efficacy has been demonstrated by both in vitro and in vivo studies [71]. Moreover, some of these inhibitors have already undergone clinical testing (Table 2). Although the exact molecular mechanisms underlying the reliance of tumors on glycolysis remain not completely understood [71], glycolysis inhibition opens feasible therapeutic windows for cancer treatment. Indeed, several small molecules have been identified and have been shown to exhibit promising anticancer activities both in vitro and in vivo, as single agents or in combination with other therapeutic modalities.
12. Hexokinase Inhibitors: 2-Deoxyglucose (2-DG)
2-Deoxyglucose (2-DG) (Figure 2) is an early glycolytic inhibitor, which has been proven to be effective at depleting cellular ATP [72, 73]. 2-DG is a glucose analogue, which is phosphorylated by the enzyme HK to 2-deoxyglucose-6-phosphate (2-DG-6-P). 2-DG-6-P cannot be further metabolized and accumulates in the cytoplasm, leading to a proximal blockade of glycolysis [73]. Several reports have shown that the cytotoxic effects of 2-DG are heterogeneous [74, 75]. The cytotoxic effects of 2-DG were found to be higher in cancer cells under hypoxic conditions or in cells with mitochondrial defects [76–79]. Recent studies have reported the therapeutic efficacy of 2-DG combined with chemotherapeutic drugs or ionizing radiation, and indeed, in both cases, the inhibitor enhanced the damage to cancer cells, while reducing the damage to normal cells [78, 79] (i.e., 2-DG in combination with cisplatin and doxorubicin had a significant cytotoxic effect in rapidly dividing cells, whereas no effect was seen in slowly growing cells [80].) 2-DG can also enhance DNA damage caused by irradiation in cancer cells [76].
13. Multiple Glycolytic Inhibitors: 3-Bromopyruvate (3-BrPA)
The metabolic blocker 3-bromopyruvate (3-BrPA) (Figure 2) is a halogenated analogue of pyruvic acid with strong alkylating properties and has received significant attention due to its remarkable antitumor activity [71, 81]. In vitro testing demonstrated that 3-BrPA inhibits glycolysis and blocks ATP production, thus causing apoptosis in a dose-dependent manner [71]. Like 2-DG, 3-BrPA exhibited a potent cytotoxic activity against cancer cells with mitochondrial respiratory defects and against cells in a hypoxic environment [82]. 3-BrPA is believed to inhibit HKII through a covalent modification at one or more cysteine residues leading to an attenuation of the glycolytic rate [83]. Further studies using radiolabelled 3-BrPA have identified the glycolytic enzyme GAPDH as the primary intracellular target of this agent [84]. The binding of 3-BrPA to GAPDH caused an inhibition of its enzyme activity and, consequently, of the glycolytic production of ATP, which led to cell death by apoptosis [85]. The antineoplastic effects of 3-BrPA resulted from a reduction in some intermediates of glycolysis, thus impairing the replenishment of anabolic reactions branching from the glycolytic pathway [86]. Indeed, the 3-BrPA-mediated inhibition of HKII could result in a reasonable reduction in ribose-5-phosphate synthesis [71]. Similarly, GAPDH inhibition could decrease the levels of its downstream metabolite, 3-phosphoglycerate, thus reducing the production of lipids and amino acids deriving from it [87]. 3-BrPA also displayed an effect on the extra-glycolytic enzyme succinate dehydrogenase (SDH) [88], which contributed to a block in ATP production and to an impairment of mitochondrial respiratory function. 3-BrPA is effective at a concentration of 100 nM, meaning that it is more potent than 2-DG, which is effective in the mM concentration range [88].
Although, many preclinical studies have confirmed its anticancer properties, the molecular targets and the mechanisms underlying 3-BrPA-induced cytotoxicity have not been completely defined thus, its application in human has not been tested by clinical trials yet.
14. Inhibition of PKM2
Inhibition of PKM2 has so far been achieved by using RNA interference (RNAi), which induced apoptosis and tumor regression, partially by enabling a reversion of the metabolic shift [89].
15. LDHA Inhibitors: (FX11 [3-Dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxilic Acid])
FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxilic acid] (FX11) (Figure 2) is a small-molecule inhibitor selective for LDHA [90]. FX11 was identified through screening a library of compounds derived from the natural product gossypol, a known antimalarial LDH inhibitor [91]. FX11 was shown to induce oxidative stress and cells death in vitro, as well as an inhibition of the progression of human lymphoma and pancreatic xenografts in vivo [92]. Additional studies have described a reduction in ATP levels and the induction of significant oxidative stress and cell death upon treatment with FX11 [92]. Several studies have documented that inhibition of LDHA can reduce cellular transformation and markedly delay tumor formation, indicating that LDHA is required for tumor progression [93, 94]. It has also been shown that FX11, when combined with FK866, another metabolic inhibitor that inhibits NAD+ synthesis through a direct inhibition of nicotinamide phosphoribosyltransferase, can induce lymphoma regression [95]. Nevertheless, the evaluation of FX11 in clinical studies has not been reported on yet.
16. PDK1 Inhibitors: Dichloroacetate
Dichloroacetate (DCA) is a mimetic form of pyruvate, and among several glycolytic inhibitors it is known to significantly decrease lactate production in myeloma cancer cell lines [96]. This is due to the ability of DCA to inhibit PDK1 [97–99], resulting in impaired phosphorylation of PDH. DCA treatment restored the activity of PDH which can supply acetyl-CoA to the TCA cycle and oxidative metabolism [98]. The antitumor activity of DCA was documented against a variety of cancer cells type derived from the lung [97], breast [100], prostate [101], endometrial [102], and colorectal cancers [103].
17. Hematological Malignancies
HMs comprise a collection of heterogenous diseases, all originating from cells from the bone marrow and the lymphatic system. The overall prevalence of haematological cancers is increasing representing the fifth most common cancer group [104]. HMs include lymphomas, leukemia, myeloproliferative neoplasms, plasma cell dyscrasias, histiocytic tumor, and dendritic cell neoplasms. The incidence of HMs increases with age (mean age at diagnosis: 63 years). There is no gold standard for hematopoietic disease classification thus; multiple methods were applied over the years. Among them, the most frequently used systems include Revised European-American classification in 1994 (REAL), French-American-British system (FAB), and World Health Organization (WHO) classification in 2001 (updated in 2008) [105]. The inability of the earliest classification, based on cellular morphology and histological architecture, to distinguish HMs subtypes led to the incorporation of two additional criteria into the REAL classification by the WHO in 2001: the immunophenotype and the genetic background.
Nowadays, the WHO classification updated in 2008 is widely used and accepted [106]. Indeed, this system classifies malignancies of the hematopoietic and lymphoid tissues based on morphological, immunophenotypic, genetic, and clinical features with the aim of increasing diagnostic accuracy. In addition, this classification has created borderline categories for cases that do not fit into a particular subgroup. When possible, the different cancer types are grouped by lineage into myeloid neoplasms, lymphoid neoplasms, and histocytic/dendritic neoplasms [105]. There are also neoplasms that show evidence of both myeloid and lymphoid differentiations, probably due to the fact that they are derived from multipotent progenitors cells, and these are then classified as neoplasms of myeloid and lymphoid lineages.
18. Myeloid Neoplasms
Myeloid neoplasms are usually derived from bone marrow committed progenitors restricted to give rise to erythrocytes, granulocytes (neutrophils, basophils, and eosinophils), monocytes, or megakaryocytes. Myeloid neoplasms are generally adult diseases presenting symptoms at a median age of 64 years. They are be subgrouped into three broad clinical classes: acute myeloid leukemias (AML), myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS). The first one, AML, has a very aggressive outcome and requires immediate therapy, whereas the clinical behaviour of MPN and MDS can be quite indolent. AML is characterised by more than 20% of myeloid blasts in the bone marrow or in the peripheral blood and is subdivided into five groups: (a) AML with recurrent genetic abnormalities, (b) AML with myelodysplasia-related changes, (c) therapy-related myeloid neoplasms, (d) AML not otherwise specified, and (e) myeloid sarcoma and myeloid proliferation related to Down syndrome.
The second myeloid neoplasms, MPN, is a group of disorders associated with the proliferation of one specific myeloid lineage (i.e., granulocytes, erythroid, megakaryocytic, or mast cells). This disease is often associated with mutations causing abnormal increases in tyrosine kinase activity and growth factor-independent proliferation of bone marrow progenitors. The MPN can be divided into (a) chronic myeloid leukemia (CML), (b) chronic neutrophilic leukemia (CNL), (c) polycythemia vera (PCV), (d) essential thrombocythemia (ET), (e) primary myelofibrosis (PMF), (f) chronic eosinophilic leukemia (CEL), (g) mastocytosis, and (h) unclassificable myeoloproliferative neoplasms (referred to as atypical MPNs). The third subtype of myeloid neoplasms, MDS, refers to disorders exhibiting dysplasia and with a variable risk of transformation to acute leukemia. Furthermore, the hematopoiesis is ineffective and results in cytopenias. Like AML and MPN, MDS is composed of several subtypes: (a) refractory cytopenia with unilineage dysplasia, (b) refractory anemia with ring sideroblasts, (c) refractory cytopenia with multlineage dysplasia, (d) refractory anemia with excess blasts, (e) unclassifiable MDS, and (f) childhood MDS.
19. Lymphoid Neoplasms
Lymphoid neoplasms are those derived from cells that develop into T lymphocytes (cytotoxic T lymphocytes, helper T lymphocytes, or regulatory T lymphocytes) or B lymphocytes. Lymphoid neoplasms are divided into 2 groups: neoplasms derived from lymphoid precursors (i.e., acute lymphoblastic leukemia/lymphoma, ALL) and neoplasms of mature lymphocytes and plasma cells. The first group is composed two main categories: precursor B lymphoblastic leukemia/lymphomas and precursor T lymphoblastic leukemia/lymphoma. Concerning the neoplasms of mature lymphocytes, the WHO grouped the diseases based on B or T cell origin. The classification of mature B cell neoplasms is based on a comparison of aberrant and normal B cell development and is divided into (a) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), (b) lymphoplasmacytic lymphoma (LPL), (c) mantle cell lymphoma (MCL), (d) B cell prolymphocitic leukemia (B-PLL), (e) follicular lymphoma (FL), (f) diffuse large B cell lymphoma (DLBCL), (g) Burkitt lymphoma/leukemia (BL), (h) marginal zone B cell lymphoma (MZL), (i) hairy cell leukemia (HCL), and (l) plasma cell myeloma/plasmacytoma. Hodgkin's disease or Hodgkin lymphoma (HL) is separated from the other B cell lymphomas based on its unique cellular composition, containing a minority of neoplastic cells in an inflammatory background. HL can be divided into two major subgroups: nodular lymphocyte predominant HL and classical HL.
The mature T cell and natural killer (NK) cell neoplasms are lymphoid neoplasms of mature T cell or NK cells including (a) peripheral T cell lymphoma (PTCL), (b) anaplastic large cell lymphoma (ALCL), (c) primary cutaneous peripheral T cell lymphomas, adult T cell leukemia-lymphoma (ATL), (d) T large granular lymphocyte leukemia (LGL), (e) T cell prolymphocytic leukemia (T-PLL), and (f) NK cell large granular lymphocyte leukemia (LGL).
The last group of HMs, according to the 2008 WHO classification, includes histiocytic/dendritic neoplasms derived from accessory antigen-presenting precursor cells (APC or dentritic cells) or connective tissue macrophages (histiocytes). Histiocytic/dendritic neoplasms are divided into 3 groups: (a) histiocytic sarcoma, (b) tumors derived from Langerhans cells, and (c) follicular dendritic sarcoma.
20. Risk Factors and Standard Protocol for HMs
There are many risk factors playing a role in HMs development. Age is the most significant risk factor, since these cancers most often occur in patients aged 60 or older. Furthermore, benzene exposure, ionizing radiation, or certain types of viral infections (i.e., HTLV1 or HIV) have been linked to the development of leukemia. The type of cancer, stage, age, sex, race, and the presence of chromosomal abnormalities are important factors in HMs treatment. Based on these factors, treatment may include chemotherapy, radiotherapy, targeted therapies, and hematopoietic stem cell transplantation. The frequent chromosomal abnormalities in HMs include gene deletions, amplifications, and translocations. The major and most important chromosomal abnormality in CML is the presence of the Philadelphia chromosome (Ph+) arising from a translocation t(9;22) resulting in the BCR/ABL (Breakpoint Cluster Region/ABelson murine Leukemia viral oncogene homolog) gene fusion. More than 85% of patients diagnosed with CML have the Ph+ chromosome. The presence of the Ph+ chromosome, in the absence of additional chromosomal changes, is associated with a good prognosis in CML. A large number of structural and numerical chromosomal changes have been described in ALL [107]. However, some of these changes occur more frequently than others. The human mixed lineage leukemia (MLL) gene on chromosome 4, the t(12;21) translocation resulting in the TEL/AML (Translocation Ets-Leukemia/Acute-Myeloid-Leukemia) gene fusion, hyperdiploidy, together with the t(9;22) translocation, which produces the BCR/ABL fusion, are the most common karyotypic abnormalities in ALL. The TEL/AML fusion gene appears to be associated with a good prognosis in ALL, while the presence of BCR/ABL has an unfavorable prognosis [108].
21. Targeting the Glycolytic Pathway in HMs
Although there are many examples of rapidly proliferating solid tumor cells that have a fundamental change in their metabolism and exhibit an increased dependency on the glycolytic pathway for ATP generation, it has been only recently reported that this phenomenon also occurs in HMs.The metabolic difference between normal cells and cancer cells provides a basis for the design of therapeutic approach to selectively kill cancer cells. So far, studies on the altered metabolism of HMs have been mainly focused on AML and ALL. The available evidence supports the hypothesis that these leukemia subtypes demonstrate a dependence on glycolysis under aerobic conditions, thus providing a potential opportunity for the use of glycolysis inhibitors in acute leukemia.
It has been published that leukemia cells, as tumor cells, shift their metabolism from oxidative phosphorylation toward the less efficient glycolysis. An evidence of this phenomenon comes from the observation that several genes involved in glucose metabolism were reported to be differentially expressed in pediatric leukemia. Expression profiling showed that the expression of HIF-1α, GLUT1, GLUT3, carbonic anhydrase 4 (CA4), and GAPDH was significantly higher in leukemic cells than in normal peripheral blood [109]. In addition leukemic cells with an increase of glycolytic rate appear to display glucocorticoid resistance, and the inhibition of glycolysis, rendered otherwise resistant leukemia cells susceptible to glucocorticoid treatment. The first generation glycolysis inhibitor, 2-DG, could reverse the glucocorticoid resistance in leukemia cells [110]. Treatment with 2-DG enhanced the chemotherapeutic effects of glucocorticoids (i.e., dexamethasone, prednisone and derivate) in particular against leukemic cells with mitochondrial defects. The phenomenon has been shown not only in cell lines but was also observed from primary leukemic cells of pediatric leukemia patients. However, clinical feasibility is limited with this compound [111] due to the high (mM) concentrations of the drug required for efficacy. In addition, recent studies indicated that 2-DG not only inhibits glycolysis and consumption of glucose to produce ATP or fatty acids but can also be metabolized though the pentose phosphate pathway (PPP). Moreover, 2-DG alters protein glycosylation, in particular by inhibiting N-glycosylation. Through the inhibition of N-glycosylation, 2-DG has been shown to kill cells in normoxia and to produce subsequent cellular stress. For this reason, other inhibitors of the enzyme HKII were tested in leukemia. 3-BrPA seems to have a greater potency but still requires a high dosage and has limited solubility and biodistribution. A report in human lymphoma and the AML cell line HL60 documented the induction of cell death upon treatment with 3-BrPA [112–114].
A recent study described a possible combinatorial treatment using an inhibitor of glycolysis (3-BrPA) and an inhibitor of electron transfer in the mitochondrial complex-III (antimycin A). Antimycin A is also a potent inhibitor of cytochrome-c-reductase. As a single agent, antimycin A was shown to induce apoptosis and to increase glycolytic rates [115, 116]. When 3-BrPA and antimycin A were combined, a dramatic decrease in the ATP levels of cancer cells was observed [117]. This study demonstrated that acute leukemia appears to be dependent on glycolysis for survival and that blockade of oxidative respiration can also have an effect on cell viability. However, the combined inhibition of glycolysis and oxidative phosphorylation led to more significant cell death. It is at present unclear whether this combinatorial treatment will also lead to toxicity in nonmalignant cells.
An alternative approach to potentiate the cytotoxic effects of glycolysis inhibitors in leukemia is the targeting of the mammalian target of rapamycin (mTOR) pathway, which is critical for cellular responses to metabolic stress [118]. The mTOR pathway plays an important role in nutrient uptake, regulation of energy metabolism, and cancer cells survival [118–120]. The targeted inhibition of both glycolysis and mTOR can cooperate to induce severe metabolic deregulation, cell death, and impaired ATP generation in cancer cells that are more dependent on glycolysis for energy production. In vitro and in vivo studies in leukemia and lymphoma cells [113, 120] demonstrated that a combination of rapamycin and 3-BrOP (3-bromo-2-oxopropionate-1-propyl ester), a cell permeable ester of 3-BrPA, effectively depleted cellular ATP [121]. Moreover, the combinatorial effect caused dephosphorylation of mTOR downstream target molecules (i.e., p70S6K) leading to alterations not only in cellular metabolism but also in survival signals. Furthermore, the simultaneous inhibition of glycolysis and the mTOR pathway is a potentially less toxic approach to target cancer cells. When ATP is depleted by glycolysis inhibition, blocking the mTOR patway further limits nutrient uptake, cell proliferation, and cell survival [121].
The sensitivity of leukemia cells to combinations of glycolytic inhibitors, such as 2-DG and 3-BrPA, and inhibitors of oxidative phosphorylation (antimycin A) or the mTOR pathway (rapamycin analogues) suggests a potential role for combinatorial therapeutic approaches in HMs. These combinations may lead to alterations not only in cellular metabolism but also in survival signal [122, 123].
Recent findings have suggested that the Warburg effect is also present in multiple myeloma (MM) [96]. For this reason, several research groups have tried to inhibit glycolysis as a novel therapeutic approach in these HMs. A recent study from Fujiwara et al. [124] described a new inhibitor of glycolysis, DCA, which promotes pyruvate oxidation and induced MM growth inhibition. The inhibition of aerobic glycolysis by DCA occurred via the downregulation of PDK1, a kinase that phosphorylates and inhibits PDH within the mitochondria. The inhibition of PDK1 and the restoration of the activity of PDH induced by DCA led to an increased supply of acetyl-CoA to the Krebs cycle and NADH electron donation to the electron transport chain [98]. An increase in electron transport chain activity causes a generation of mitochondrial reactive oxygen species (ROS) which contribute to generating a loss of mitochondrial membrane potential and ultimately the suppression of cell proliferation.
The standard therapy for patients with MM is based on bortezomib, which induces a strong apoptotic response in myeloma cells [96]. However, plasma cells can become resistant to apoptosis, a phenomenon which is linked to aerobic glycolysis and predicts a poor clinical outcome in patients. Fujiwara et al. described that a combinatorial treatment of MM with bortezomib and DCA significantly increased superoxide production and induced apoptosis. In addition the authors performed an in vivo study with myeloma-bearing mice. A significantly prolonged survival of myeloma-bearing mice was observed upon treatment with the combinatorial therapy (DCA + bortezomib) [96], when compared with control mice or mice treated only with a monotherapy. Thus, inhibition of glycolysis increased the sensitivity of MM cells to conventional chemotherapy in vitro and improved the survival of myeloma-bearing mice in vivo.
22. Conclusion
Targeting glycolysis has emerged as a potential novel approach to develop targeted therapies in HMs. However, additional studies are needed to investigate the molecular mechanisms of the dependency of HMs on glycolysis and its importance in chemoresistance. Since the use of cell lines from leukemia, lymphoma, or MM has certain limitations, such as metabolic adaptation and changes in the rates of cell growth and proliferation, it will be important to also test combinatorial strategies involving glycolytic inhibitors in primary samples from patients with HMs. If successful, these studies will warrant further investigations in vivo in appropriate models of HMs. Such work is a prerequisite for the successful transition of targeted therapies using inhibitors of glycolysis to perform clinical testing in patients with HMs.
Work in the author's laboratory is supported by Grants from the European Union's FP7 (ASSET, project number: 259348 and LUNGTARGET, project number: 259770), the Swiss National Science Foundation (Grant 31003A-120294 and 31003A-146464), the Fondation FORCE, the Novartis Stiftung für Medizinisch-Biologische Forschung, the Jubiläumsstiftung der Schweizerischen Mobiliar Genossenschaft, the Stiftung zur Krebsbekämpfung, the Huggenberger-Bischoff Stiftung zur Krebsforschung, the UniBern Forschungsstiftung, and the Stiftung für klinisch-experimentelle Tumorforschung, Bern. Zaira Leni and Geetha Parakkal are members of the Graduate School of Cellular and Biomedical Science of University of Bern.
- M. R. Stratton, P. J. Campbell, and P. A. Futreal, "The cancer genome," Nature, vol. 458, no. 7239, pp. 719–724, 2009. View at Publisher · View at Google Scholar · View at Scopus
- T. J. Hudson, W. Anderson, A. Artez, et al., "International network of cancer genome projects," Nature, vol. 464, pp. 993–998, 2010.
- M. J. Jones and P. V. Jallepalli, "Chromothripsis: chromosomes in crisis," Developmental Cell, vol. 23, pp. 908–917, 2012.
- A. Ramanathan, C. Wang, and S. L. Schreiber, "Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 17, pp. 5992–5997, 2005. View at Publisher · View at Google Scholar · View at Scopus
- T. Wang, C. Marquardt, and J. Foker, "Aerobic glycolysis during lymphocyte proliferation," Nature, vol. 261, no. 5562, pp. 702–705, 1976. View at Scopus
- D. E. Bauer, M. H. Harris, D. R. Plas et al., "Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand," FASEB Journal, vol. 18, no. 11, pp. 1303–1305, 2004. View at Publisher · View at Google Scholar · View at Scopus
- N. Oyama, H. Akino, Y. Suzuki et al., "Prognostic value of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography imaging for patients with prostate cancer," Molecular Imaging and Biology, vol. 4, no. 1, pp. 99–104, 2002. View at Publisher · View at Google Scholar · View at Scopus
- S. L. C. Tagg, P. A. Foster, M. P. Leese et al., "2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer," British Journal of Cancer, vol. 99, no. 11, pp. 1842–1848, 2008. View at Publisher · View at Google Scholar · View at Scopus
- E. Poteet, G. R. Choudhury, A. Winters, W. Li, M. G. Ryou, R. Liu, et al., "Reversing the warburg effect as a treatment for glioblastoma," Journal of Biological Chemistry, vol. 288, pp. 9153–9164, 2013.
- X. D. Zhang, E. Deslandes, M. Villedieu et al., "Effect of 2-deoxy-D-glucose on various malignant cell lines in vitro," Anticancer Research, vol. 26, no. 5, pp. 3561–3566, 2006. View at Scopus
- J. Son, C. A. Lyssiotis, H. Ying, et al., "Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway," Nature, vol. 496, pp. 101–105, 2013.
- O. Warburg, "On the origin of cancer cells," Science, vol. 123, no. 3191, pp. 309–314, 1956. View at Scopus
- O. Warburg, "Über den stoffwechsel der carcinomzelle," Die Naturwissenschaften, vol. 12, no. 50, pp. 1131–1137, 1924. View at Publisher · View at Google Scholar · View at Scopus
- A. Vazquez, J. Liu, Y. Zhou, and Z. N. Oltvai, "Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited," BMC Systems Biology, vol. 4, article 58, 2010. View at Publisher · View at Google Scholar · View at Scopus
- G. Maschek, N. Savaraj, W. Priebe et al., "2-deoxy-D-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo," Cancer Research, vol. 64, no. 1, pp. 31–34, 2004. View at Publisher · View at Google Scholar · View at Scopus
- M. De Lena, V. Lorusso, A. Latorre et al., "Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study," European Journal of Cancer, vol. 37, no. 3, pp. 364–368, 2001. View at Publisher · View at Google Scholar · View at Scopus
- M. Fanciulli, T. Bruno, A. Giovannelli et al., "Energy metabolism of human LoVo colon carcinoma cells: correlation to drug resistance and influence of lonidamine," Clinical Cancer Research, vol. 6, no. 4, pp. 1590–1597, 2000. View at Scopus
- A. Godoy, V. Ulloa, F. Rodríguez et al., "Differential subcellular distribution of glucose transporters GLUT1-6 and GLUT9 in human cancer: ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues," Journal of Cellular Physiology, vol. 207, no. 3, pp. 614–627, 2006. View at Publisher · View at Google Scholar · View at Scopus
- L. Szablewski, "Expression of glucose transporters in cancers," Biochimica et Biophysica Acta, vol. 1835, pp. 164–169, 2013.
- R. Airley, A. Evans, A. Mobasheri, and S. M. Hewitt, "Glucose transporter Glut-1 is detectable in peri-necrotic regions in many human tumor types but not normal tissues: study using tissue microarrays," Annals of Anatomy, vol. 192, no. 3, pp. 133–138, 2010. View at Publisher · View at Google Scholar · View at Scopus
- R. Moreno-Sánchez, S. Rodríguez-Enríquez, A. Marín-Hernández, and E. Saavedra, "Energy metabolism in tumor cells," FEBS Journal, vol. 274, no. 6, pp. 1393–1418, 2007. View at Publisher · View at Google Scholar · View at Scopus
- J. E. Wilson, "Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function," Journal of Experimental Biology, vol. 206, no. 12, pp. 2049–2057, 2003. View at Publisher · View at Google Scholar · View at Scopus
- E. Bustamante and P. L. Pedersen, "High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase," Proceedings of the National Academy of Sciences of the United States of America, vol. 74, no. 9, pp. 3735–3739, 1977. View at Scopus
- K. K. Arora, M. Fanciulli, and P. L. Pedersen, "Glucose phosphorylation in tumor cells. Cloning, sequencing, and overexpression in active form of a full-length cDNA encoding a mitochondrial bindable form of hexokinase," Journal of Biological Chemistry, vol. 265, no. 11, pp. 6481–6488, 1990. View at Scopus
- A. Rempel, S. P. Mathupala, C. A. Griffin, A. L. Hawkins, and P. L. Pedersen, "Glucose catabolism in cancer cells: amplification of the gene encoding type II hexokinase," Cancer Research, vol. 56, no. 11, pp. 2468–2471, 1996. View at Scopus
- E. Pirinen, S. Heikkinen, M. Malkki, S. S. Deeb, J. Jänne, and M. Laakso, "Analysis of the human hexokinase II promoter in vivo: lack of insulin response within 4.0 kb," Biochimica et Biophysica Acta, vol. 1676, no. 2, pp. 149–154, 2004. View at Publisher · View at Google Scholar · View at Scopus
- G. L. Semenza, "Hif-1 and human disease: one highly involved factor," Genes and Development, vol. 14, no. 16, pp. 1983–1991, 2000. View at Scopus
- P. L. Pedersen, "Warburg, me and Hexokinase 2: multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen," Journal of Bioenergetics and Biomembranes, vol. 39, no. 3, pp. 211–222, 2007. View at Publisher · View at Google Scholar · View at Scopus
- G. Kroemer, L. Galluzzi, and C. Brenner, "Mitochondrial membrane permeabilization in cell death," Physiological Reviews, vol. 87, no. 1, pp. 99–163, 2007. View at Publisher · View at Google Scholar · View at Scopus
- X. Filella, R. Molina, J. Jo, E. Mas, and A. M. Ballesta, "Serum phosphohexose isomerase activities in patients with colorectal cancer," Tumor Biology, vol. 12, no. 6, pp. 360–367, 1991. View at Scopus
- S. Tsutsumi, T. Fukasawa, H. Yamauchi et al., "Phosphoglucose isomerase enhances colorectal cancer metastasis," International Journal of Oncology, vol. 35, no. 5, pp. 1117–1121, 2009. View at Publisher · View at Google Scholar · View at Scopus
- G. Weber, "Enzymology of cancer cells (second of two parts)," The New England Journal of Medicine, vol. 296, no. 10, pp. 541–551, 1977. View at Scopus
- E. Van Schaftingen, M. F. Jett, L. Jue, and H. G. Hers, "Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors," Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 6, pp. 3483–3486, 1981. View at Scopus
- A. Hennipman, J. Smits, B. Van Oirschot et al., "Glycolytic enzymes in breast cancer, benign breast disease and normal breast tissue," Tumor Biology, vol. 8, no. 5, pp. 251–263, 1987. View at Scopus
- A. Hennipman, B. A. Van Oirschot, J. Smits, G. Rijksen, and G. E. J. Staal, "Glycolytic enzyme activities in breast cancer metastases," Tumor Biology, vol. 9, no. 5, pp. 241–248, 1988. View at Scopus
- C. Sánchez-Martínez and J. Aragón, "Analysis of phosphofructokinase subunits and isozymes in ascites tumor cells and its original tissue, murine mammary gland," FEBS Letters, vol. 409, no. 1, pp. 86–90, 1997. View at Publisher · View at Google Scholar · View at Scopus
- A. Yalcin, S. Telang, B. Clem, and J. Chesney, "Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer," Experimental and Molecular Pathology, vol. 86, no. 3, pp. 174–179, 2009. View at Publisher · View at Google Scholar · View at Scopus
- W. Yi, P. M. Clark, D. E. Mason, et al., "Phosphofructokinase 1 glycosylation regulates cell growth and metabolism," Science, vol. 337, pp. 975–980, 2012.
- D. Hugo-Wissemann, I. Anundi, W. Lauchart, R. Viebahn, and H. De Groot, "Differences in glycolytic capacity and hypoxia tolerance between hepatoma cells and hepatocytes," Hepatology, vol. 13, no. 2, pp. 297–303, 1991. View at Publisher · View at Google Scholar · View at Scopus
- Y. Gong, L. Cui, and G. Y. Minuk, "Comparison of glyceraldehyde-3-phosphate dehydrogenase and 28S-ribosomal RNA gene expression in human hepatocellular carcinoma," Hepatology, vol. 23, no. 4, pp. 734–737, 1996. View at Publisher · View at Google Scholar · View at Scopus
- M. A. Sirover, "New nuclear functions of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in mammalian cells," Journal of Cellular Biochemistry, vol. 95, no. 1, pp. 45–52, 2005. View at Publisher · View at Google Scholar · View at Scopus
- M. Perucho, J. Salas, and M. L. Salas, "Study of the interaction of glyceraldehyde-3-phosphate dehydrogenase with DNA," BBA Section Nucleic Acids And Protein Synthesis, vol. 606, no. 2, pp. 181–195, 1980. View at Scopus
- F. Grosse, H.-P. Nasheuer, S. Scholtissek, and U. Schomburg, "Lactate dehydrogenase and glyceraldehyde-phosphate dehydrogenase are single-stranded DNA-binding proteins that affect the DNA-polymerase-α-primase complex," European Journal of Biochemistry, vol. 160, no. 3, pp. 459–467, 1986. View at Scopus
- E. Nagy, T. Henics, M. Eckert, A. Miseta, R. N. Lightowlers, and M. Kellermayer, "Identification of the NAD+-binding fold of glyceraldehyde-3-phosphate dehydrogenase as a novel RNA-binding domain," Biochemical and Biophysical Research Communications, vol. 275, no. 2, pp. 253–260, 2000. View at Publisher · View at Google Scholar · View at Scopus
- T. J. C. van Berkel, H. R. De Jonge, J. F. Koster, and W. C. Hulsmann, "Kinetic evidence for the presence of two forms of M2 type pyruvate kinase in rat small intestine," Biochemical and Biophysical Research Communications, vol. 60, no. 1, pp. 398–405, 1974. View at Scopus
- H. R. Christofk, M. G. Vander Heiden, M. H. Harris et al., "The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth," Nature, vol. 452, no. 7184, pp. 230–233, 2008. View at Publisher · View at Google Scholar · View at Scopus
- U. Brinck, E. Eigenbrodt, M. Oehmke, S. Mazurek, and G. Fischer, "L- and M2- pyruvate kinase expression in renal cell carcinomas and their metastases," Virchows Archiv, vol. 424, no. 2, pp. 177–185, 1994. View at Scopus
- D. Lüftner, J. Mesterharm, C. Akrivakis et al., "Tumor type M2 pyruvate kinase expression in advanced breast cancer," Anticancer Research, vol. 20, no. 6, pp. 5077–5082, 2000. View at Scopus
- S. Mazurek, C. B. Boschek, F. Hugo, and E. Eigenbrodt, "Pyruvate kinase type M2 and its role in tumor growth and spreading," Seminars in Cancer Biology, vol. 15, no. 4, pp. 300–308, 2005. View at Publisher · View at Google Scholar · View at Scopus
- J. Ye, A. Mancuso, X. Tong, et al., "Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation," Proceedings of the National Academy of Sciences of the United States of America, vol. 109, pp. 6904–6909, 2012.
- J. D. Laughton, P. Bittar, Y. Charnay et al., "Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of lactate dehydrogenase 5 and pyruvate dehydrogenase," BMC Neuroscience, vol. 8, article 35, 2007. View at Publisher · View at Google Scholar · View at Scopus
- A. Sevinc, R. Sari, and E. Fadillioglu, "The utility of lactate dehydrogenase isoenzyme pattern in the diagnostic evaluation of malignant and nonmalignant ascites," Journal of the National Medical Association, vol. 97, no. 1, pp. 79–84, 2005. View at Scopus
- M. I. Koukourakis, A. Giatromanolaki, C. Simopoulos, A. Polychronidis, and E. Sivridis, "Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer," Clinical and Experimental Metastasis, vol. 22, no. 1, pp. 25–30, 2005. View at Publisher · View at Google Scholar · View at Scopus
- Y. Kolev, H. Uetake, Y. Takagi, and K. Sugihara, "Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1α) pathway, angiogenic factors production and poor prognosis," Annals of Surgical Oncology, vol. 15, no. 8, pp. 2336–2344, 2008. View at Publisher · View at Google Scholar · View at Scopus
- F. Farabegoli, M. Vettraino, M. Manerba, et al., "Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways," European Journal of Pharmaceutical Sciences, vol. 47, pp. 729–738, 2012.
- Z.-Y. Wang, T. Y. Loo, J.-G. Shen et al., "LDH-A silencing suppresses breast cancer tumorigenicity through induction of oxidative stress mediated mitochondrial pathway apoptosis," Breast Cancer Research and Treatment, vol. 131, no. 3, pp. 791–800, 2012. View at Publisher · View at Google Scholar · View at Scopus
- H. Yang, R.-G. Lang, F.-F. Liu et al., "Primary lymphoma of breast: a clinicopathologic and prognostic study of 40 cases," Zhonghua Bing Li Xue Za Zhi, vol. 40, no. 2, pp. 79–84, 2011. View at Scopus
- C. A. Wu, Y. Chao, S. G. Shiah, and W. W. Lin, "Nutrient deprivation induces the Warburg effect through ROS/AMPK-dependent activation of pyruvate dehydrogenase kinase," Biochimica et Biophysica Acta, vol. 1833, pp. 1147–1156, 2013.
- D. S. Kerr, "Treatment of mitochondrial electron transport chain disorders: a review of clinical trials over the past decade," Molecular Genetics and Metabolism, vol. 99, no. 3, pp. 246–255, 2010. View at Publisher · View at Google Scholar · View at Scopus
- J.-W. Kim and C. V. Dang, "Cancer's molecular sweet tooth and the warburg effect," Cancer Research, vol. 66, no. 18, pp. 8927–8930, 2006. View at Publisher · View at Google Scholar · View at Scopus
- G. Sutendra and E. D. Michelakis, "Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology," Frontiers in Oncology, vol. 3, article 38, 2013.
- G. Kroemer and J. Pouyssegur, "Tumor cell metabolism: cancer's achilles' heel," Cancer Cell, vol. 13, no. 6, pp. 472–482, 2008. View at Publisher · View at Google Scholar · View at Scopus
- R. A. Gatenby and R. J. Gillies, "Why do cancers have high aerobic glycolysis?" Nature Reviews Cancer, vol. 4, no. 11, pp. 891–899, 2004. View at Publisher · View at Google Scholar · View at Scopus
- G. L. Semenza, "HIF-1: upstream and downstream of cancer metabolism," Current Opinion in Genetics and Development, vol. 20, no. 1, pp. 51–56, 2010. View at Publisher · View at Google Scholar · View at Scopus
- G. L. Semenza, "Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy," Trends in Pharmacological Sciences, vol. 33, no. 4, pp. 207–214, 2012. View at Publisher · View at Google Scholar · View at Scopus
- J. D. Gordan, C. B. Thompson, and M. C. Simon, "HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation," Cancer Cell, vol. 12, no. 2, pp. 108–113, 2007. View at Publisher · View at Google Scholar · View at Scopus
- R. C. Osthus, H. Shim, S. Kim et al., "Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc," Journal of Biological Chemistry, vol. 275, no. 29, pp. 21797–21800, 2000. View at Publisher · View at Google Scholar · View at Scopus
- H. Shim, C. Dolde, B. C. Lewis, et al., "c-Myc transactivation of LDH-A: implications for tumor metabolism and growth," Proceedings of the National Academy of Sciences of the United States of America, vol. 94, pp. 6658–6663, 1997.
- K. H. Vousden and K. M. Ryan, "P53 and metabolism," Nature Reviews Cancer, vol. 9, no. 10, pp. 691–700, 2009. View at Publisher · View at Google Scholar · View at Scopus
- S. J. Yeung, J. Pan, and M.-H. Lee, "Roles of p53, MYC and HIF-1 in regulating glycolysis—the seventh hallmark of cancer," Cellular and Molecular Life Sciences, vol. 65, no. 24, pp. 3981–3999, 2008. View at Publisher · View at Google Scholar · View at Scopus
- S. Cardaci, E. Desideri, and M. R. Ciriolo, "Targeting aerobic glycolysis: 3-Bromopyruvate as a promising anticancer drug," Journal of Bioenergetics and Biomembranes, vol. 44, no. 1, pp. 17–29, 2012. View at Publisher · View at Google Scholar · View at Scopus
- C. Sinthupibulyakit, W. Ittarat, W. H. St. Clair, and D. K. St. Clair, "p53 protects lung cancer cells against metabolic stress," International Journal of Oncology, vol. 37, no. 6, pp. 1575–1581, 2010. View at Publisher · View at Google Scholar · View at Scopus
- F. Aghaee, J. Pirayesh Islamian, and B. Baradaran, "Enhanced radiosensitivity and chemosensitivity of breast cancer cells by 2-deoxy-d-glucose in combination therapy," Journal of Breast Cancer, vol. 15, pp. 141–147, 2012.
- F. Zhang and R. L. Aft, "Chemosensitizing and cytotoxic effects of 2-deoxy-D-glucose on breast cancer cells," Journal of Cancer Research and Therapeutics, vol. 5, pp. S41–S43, 2009. View at Scopus
- C. Sinthupibulyakit, K. R. Grimes, F. E. Domann et al., "p53 is an important factor for the radiosensitization effect of 2-deoxy-D-glucose," International Journal of Oncology, vol. 35, no. 3, pp. 609–615, 2009. View at Publisher · View at Google Scholar · View at Scopus
- H. Pelicano, D. S. Martin, R.-H. Xu, and P. Huang, "Glycolysis inhibition for anticancer treatment," Oncogene, vol. 25, no. 34, pp. 4633–4646, 2006. View at Publisher · View at Google Scholar · View at Scopus
- S. Ramírez-Peinado, F. Alcázar-Limones, L. Lagares-Tena et al., "2-Deoxyglucose induces Noxa-dependent apoptosis in alveolar rhabdomyosarcoma," Cancer Research, vol. 71, no. 21, pp. 6796–6806, 2011. View at Publisher · View at Google Scholar · View at Scopus
- V. K. Kalia, S. Prabhakara, and V. Narayanan, "Modulation of cellular radiation responses by 2-deoxy-D-glucose and other glycolytic inhibitors: implications for cancer therapy," Journal of Cancer Research and Therapeutics, vol. 5, pp. S57–S60, 2009. View at Scopus
- B. S. Dwarakanath, "Cytotoxicity, radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucose in vitro," Journal of Cancer Research and Therapeutics, vol. 5, pp. S27–S31, 2009. View at Scopus
- I. M. Ahmad, E. H. Mustafa, N. H. Mustafa, L. H. Tahtamouni, and M. Y. Abdalla, "2DG enhances the susceptibility of breast cancer cells to doxorubicin," Central European Journal of Biology, vol. 5, no. 6, pp. 739–748, 2010. View at Publisher · View at Google Scholar · View at Scopus
- P. L. Pedersen, "3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective "small molecule" anti-cancer agent taken from labside to bedside: introduction to a special issue," Journal of Bioenergetics and Biomembranes, vol. 44, no. 1, pp. 1–6, 2012. View at Publisher · View at Google Scholar · View at Scopus
- R.-H. Xu, H. Pelicano, Y. Zhou et al., "Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia," Cancer Research, vol. 65, no. 2, pp. 613–621, 2005. View at Scopus
- A. Nakano, H. Miki, S. Nakamura et al., "Up-regulation of hexokinaseII in myeloma cells: targeting myeloma cells with 3-bromopyruvate," Journal of Bioenergetics and Biomembranes, vol. 44, no. 1, pp. 31–38, 2012. View at Publisher · View at Google Scholar · View at Scopus
- S. Ganapathy-Kanniappan, J.-F. H. Geschwind, R. Kunjithapatham et al., "Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is pyruvylated during 3-bromopyruvate mediated cancer cell death," Anticancer Research, vol. 29, no. 12, pp. 4909–4918, 2009. View at Scopus
- Z. Chen, W. Lu, C. Garcia-Prieto, and P. Huang, "The Warburg effect and its cancer therapeutic implications," Journal of Bioenergetics and Biomembranes, vol. 39, no. 3, pp. 267–274, 2007. View at Publisher · View at Google Scholar · View at Scopus
- S. Ganapathy-Kanniappan, R. Kunjithapatham, and J. F. Geschwind, "Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting," Anticancer Research, vol. 33, pp. 13–20, 2013.
- A. P. Periera da Silva, T. El-Bacha, N. Kyaw et al., "Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate," Biochemical Journal, vol. 417, no. 3, pp. 717–726, 2009. View at Publisher · View at Google Scholar · View at Scopus
- C. Rodrigues-Ferreira, A. P. P. Da Silva, and A. Galina, "Effect of the antitumoral alkylating agent 3-bromopyruvate on mitochondrial respiration: role of mitochondrially bound hexokinase," Journal of Bioenergetics and Biomembranes, vol. 44, no. 1, pp. 39–49, 2012. View at Publisher · View at Google Scholar · View at Scopus
- M. S. Goldberg and P. A. Sharp, "Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression," Journal of Experimental Medicine, vol. 209, no. 2, pp. 217–224, 2012. View at Publisher · View at Google Scholar · View at Scopus
- P. E. Porporato, S. Dhup, R. K. Dadhich, et al., "Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review," Frontiers in Pharmacology, vol. 2, article 49, 2011.
- Y. Yu, J. A. Deck, L. A. Hunsaker et al., "Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4," Biochemical Pharmacology, vol. 62, no. 1, pp. 81–89, 2001. View at Publisher · View at Google Scholar · View at Scopus
- A. Le, C. R. Cooper, A. M. Gouw, et al., "Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression," Proceedings of the National Academy of Sciences of the United States of America, vol. 107, pp. 2037–2042, 2010.
- V. R. Fantin, J. St-Pierre, and P. Leder, "Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance," Cancer Cell, vol. 9, no. 6, pp. 425–434, 2006. View at Publisher · View at Google Scholar · View at Scopus
- H. Xie, V. A. Valera, M. J. Merino et al., "LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer," Molecular Cancer Therapeutics, vol. 8, no. 3, pp. 626–635, 2009. View at Publisher · View at Google Scholar · View at Scopus
- A. Nahimana, A. Attinger, D. Aubry et al., "The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies," Blood, vol. 113, no. 14, pp. 3276–3286, 2009. View at Publisher · View at Google Scholar · View at Scopus
- W. Y. Sanchez, S. L. McGee, T. Connor, et al., "Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib," British Journal of Cancer, vol. 108, pp. 1624–1633, 2013.
- S. Bonnet, S. L. Archer, J. Allalunis-Turner et al., "A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth," Cancer Cell, vol. 11, no. 1, pp. 37–51, 2007. View at Publisher · View at Google Scholar · View at Scopus
- E. D. Michelakis, L. Webster, and J. R. Mackey, "Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer," British Journal of Cancer, vol. 99, no. 7, pp. 989–994, 2008. View at Publisher · View at Google Scholar · View at Scopus
- B. M. Madhok, S. Yeluri, S. L. Perry, T. A. Hughes, and D. G. Jayne, "Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells," British Journal of Cancer, vol. 102, no. 12, pp. 1746–1752, 2010. View at Publisher · View at Google Scholar · View at Scopus
- R. C. Sun, M. Fadia, J. E. Dahlstrom, C. R. Parish, P. G. Board, and A. C. Blackburn, "Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo," Breast Cancer Research and Treatment, vol. 120, no. 1, pp. 253–260, 2010. View at Publisher · View at Google Scholar · View at Scopus
- W. Cao, S. Yacoub, K. T. Shiverick et al., "Dichloroacetate (DCA) sensitizes both wild-type and over expressing bcl-2 prostate cancer cells in vitro to radiation," Prostate, vol. 68, no. 11, pp. 1223–1231, 2008. View at Publisher · View at Google Scholar · View at Scopus
- J. Y. Y. Wong, G. S. Huggins, M. Debidda, N. C. Munshi, and I. De Vivo, "Dichloroacetate induces apoptosis in endometrial cancer cells," Gynecologic Oncology, vol. 109, no. 3, pp. 394–402, 2008. View at Publisher · View at Google Scholar · View at Scopus
- H. Liang, J. Tong, G. Xie, J. He, J. Li, and F. Pan, "Synergistic antitumor effect of dichloroacetate in combination with 5-fluorouracil in colorectal cancer," Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 740564, 7 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
- D. Rodriguez-Abreu, A. Bordoni, and E. Zucca, "Epidemiology of hematological malignancies," Annals of Oncology, vol. 18, no. 1, pp. I3–I8, 2007. View at Publisher · View at Google Scholar · View at Scopus
- E. Campo, S. H. Swerdlow, N. L. Harris, S. Pileri, H. Stein, and E. S. Jaffe, "The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications," Blood, vol. 117, no. 19, pp. 5019–5032, 2011. View at Publisher · View at Google Scholar · View at Scopus
- J. Vardiman, "The classification of MDS: from FAB to WHO and beyond," Leukemia Research, vol. 36, pp. 1453–1458, 2012.
- J. A. Martinez-Climent, "Molecular cytogenetics of childhood hematological malignancies," Leukemia, vol. 11, no. 12, pp. 1999–2021, 1997. View at Scopus
- S. A. Shurtleff, A. Buijs, F. G. Behm et al., "TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis," Leukemia, vol. 9, no. 12, pp. 1985–1989, 1995. View at Scopus
- J. M. Boag, A. H. Beesley, M. J. Firth et al., "Altered glucose metabolism in childhood pre-B acute lymphoblastic leukaemia," Leukemia, vol. 20, no. 10, pp. 1731–1737, 2006. View at Publisher · View at Google Scholar · View at Scopus
- E. Hulleman, K. M. Kazemier, A. Holleman et al., "Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells," Blood, vol. 113, no. 9, pp. 2014–2021, 2009. View at Publisher · View at Google Scholar · View at Scopus
- M. Kurtoglu, J. C. Maher, and T. J. Lampidis, "Differential toxic mechanisms of 2-deoxy-D-glucose versus 2-fluorodeoxy-D-glucose in hypoxic and normoxic tumor cells," Antioxidants and Redox Signaling, vol. 9, no. 9, pp. 1383–1390, 2007. View at Publisher · View at Google Scholar · View at Scopus
- Y. H. Ko, B. L. Smith, Y. Wang et al., "Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP," Biochemical and Biophysical Research Communications, vol. 324, no. 1, pp. 269–275, 2004. View at Publisher · View at Google Scholar · View at Scopus
- R.-H. Xu, H. Pelicano, H. Zhang, F. J. Giles, M. J. Keating, and P. Huang, "Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells," Leukemia, vol. 19, no. 12, pp. 2153–2158, 2005. View at Publisher · View at Google Scholar · View at Scopus
- P. M. Herst, E. L. Hesketh, D. S. Ritchie, and M. V. Berridge, "Glycolytic metabolism confers resistance to combined all-trans retinoic acid and arsenic trioxide-induced apoptosis in HL60ρ0 cells," Leukemia Research, vol. 32, no. 2, pp. 327–333, 2008. View at Publisher · View at Google Scholar · View at Scopus
- X. Cao, L. Fang, S. Gibbs et al., "Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia," Cancer Chemotherapy and Pharmacology, vol. 59, no. 4, pp. 495–505, 2007. View at Publisher · View at Google Scholar · View at Scopus
- S.-P. Tzung, K. M. Kim, G. Basãez et al., "Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3," Nature Cell Biology, vol. 3, no. 2, pp. 183–191, 2001. View at Publisher · View at Google Scholar · View at Scopus
- W.-H. Park, Y.-W. Han, S.-W. Kim, S.-H. Kim, K.-W. Cho, and S.-Z. Kim, "Antimycin A induces apoptosis in As4.1 juxtaglomerular cells," Cancer Letters, vol. 251, no. 1, pp. 68–77, 2007. View at Publisher · View at Google Scholar · View at Scopus
- A. Panwalkar, S. Verstovsek, and F. J. Giles, "Mammalian target of rapamycin inhibition as therapy for hematologic malignancies," Cancer, vol. 100, no. 4, pp. 657–666, 2004. View at Publisher · View at Google Scholar · View at Scopus
- J. E. Dancey, "Inhibitors of the mammalian target of rapamycin," Expert Opinion on Investigational Drugs, vol. 14, no. 3, pp. 313–328, 2005. View at Publisher · View at Google Scholar · View at Scopus
- V. I. Brown, J. Fang, K. Alcorn et al., "Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling," Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 25, pp. 15113–15118, 2003. View at Publisher · View at Google Scholar · View at Scopus
- L. J. Akers, W. Fang, A. G. Levy, A. R. Franklin, P. Huang, and P. A. Zweidler-McKay, "Targeting glycolysis in leukemia: a novel inhibitor 3-BrOP in combination with rapamycin," Leukemia Research, vol. 35, no. 6, pp. 814–820, 2011. View at Publisher · View at Google Scholar · View at Scopus
- L. A. Pradelli, M. Bénéteau, C. Chauvin et al., "Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation," Oncogene, vol. 29, no. 11, pp. 1641–1652, 2010. View at Publisher · View at Google Scholar · View at Scopus
- K. Suganuma, H. Miwa, N. Imai et al., "Energy metabolism of leukemia cells: glycolysis versus oxidative phosphorylation," Leukemia and Lymphoma, vol. 51, no. 11, pp. 2112–2119, 2010. View at Publisher · View at Google Scholar · View at Scopus
- S. Fujiwara, Y. Kawano, H. Yuki, et al., "PDK1 inhibition is a novel therapeutic target in multiple myeloma," British Journal of Cancer, vol. 108, pp. 170–178, 2013.
- A. Krzeslak, K. Wojcik-Krowiranda, E. Forma, et al., "Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers," Pathology and Oncology Research, vol. 18, pp. 721–728, 2012.
- A. Wolf, S. Agnihotri, J. Micallef et al., "Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme," Journal of Experimental Medicine, vol. 208, no. 2, pp. 313–326, 2011. View at Publisher · View at Google Scholar · View at Scopus
- C. Rubie, K. Kempf, J. Hans et al., "Housekeeping gene variability in normal and cancerous colorectal, pancreatic, esophageal, gastric and hepatic tissues," Molecular and Cellular Probes, vol. 19, no. 2, pp. 101–109, 2005. View at Publisher · View at Google Scholar · View at Scopus
- D. M. Parkin, F. Bray, J. Ferlay, and P. Pisani, "Global cancer statistics, 2002," Ca-A Cancer Journal for Clinicians, vol. 55, no. 2, pp. 74–108, 2005. View at Scopus
- P. A. Nguewa, J. Agorreta, D. Blanco et al., "Identification of Importin 8 (IPO8) as the most accurate reference gene for the clinicopathological analysis of lung specimens," BMC Molecular Biology, vol. 9, article 103, 2008. View at Publisher · View at Google Scholar · View at Scopus
- M. Jung, A. Ramankulov, J. Roigas et al., "In search of suitable reference genes for gene expression studies of human renal cell carcinoma by real-time PCR," BMC Molecular Biology, vol. 8, article 47, 2007. View at Publisher · View at Google Scholar · View at Scopus
- F. Révillion, V. Pawlowski, L. Hornez, and J.-P. Peyrat, "Glyceraldehyde-3-phosphate dehydrogenase gene expression in human breast cancer," European Journal of Cancer, vol. 36, no. 8, pp. 1038–1042, 2000. View at Publisher · View at Google Scholar · View at Scopus
- C. Rubie, K. Kempf, J. Hans et al., "Housekeeping gene variability in normal and cancerous colorectal, pancreatic, esophageal, gastric and hepatic tissues," Molecular and Cellular Probes, vol. 19, no. 2, pp. 101–109, 2005. View at Publisher · View at Google Scholar · View at Scopus
- S. Waxman and E. Wurmbach, "De-regulation of common housekeeping genes in hepatocellular carcinoma," BMC Genomics, vol. 8, article 243, 2007. View at Publisher · View at Google Scholar · View at Scopus
- L. E. Raez, K. Papadopoulos, A. D. Ricart, et al., "A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors," Cancer Chemotherapy and Pharmacology, vol. 71, pp. 523–530, 2013.
- M. Stein, H. Lin, C. Jeyamohan et al., "Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies," Prostate, vol. 70, no. 13, pp. 1388–1394, 2010. View at Publisher · View at Google Scholar · View at Scopus


text:
State Treasure - Maine
From page 41 of the April, 2012 issue of Lost Treasure
Copyright © 2012 Lost Treasure, Inc. all rights reserved
Island Treasures
Tales of treasure and buried caches are prolific throughout the many islands off Maine's shores. Legendary pirate treasures are said to be buried among these islands, along with shipwreck treasures, outlaw caches, and prohibition era bootlegger's caches.
Though plenty of treasure legends are more folklore than fact, the number of known recoveries where treasure has been unearthed on several Maine Islands is testimony to the fact that they were popular safe-havens for pirates, fugitives and outlaws while hosting various enterprises over the years, including piracy, smuggling, bootlegging, and salvage.Cliff Island (CUMBERLAND COUNTY) – Captain Keiff, as he was known, retired alone to a small secluded hut on Cliff Island. Said to have amassed his fortune from years of plundering ships on the Atlantic, Capt. Keiff was a pirate of a different sort. In this case, the good captain had no ship and therefore no need of a crew.
Instead, Keiff would tie a lantern around his horse's neck and ride up and down along the beach at night attempting to vector ships inbound.
Misguided by the light, ships at sea would wreck on the reefs surrounding the tiny island; generally the sea claimed the lives of all onboard.
Should any lucky survivors reach the safety of land Keiff made quick work of them as they praised the Lord and grasped the white sands that meant grace had spared their lives.
With the light work done, the good captain now claimed salvage rights to the wreck and was free to salvage the ship's cargo, stores and treasure at his leisure.
Keiff is reported to have lived off the provisions and supplies provided from his salvaging operations and spent very little of his money. With no family and few opportunities to spend his plunder, much of Capt. Keiff's treasure is believed to remain buried somewhere on Cliff Island.Manana Island (LINCOLN COUNTY) – A fishing boat stopped here in 1900 for some down time. Several fishermen onboard, including the captain, opted to relax by pairing off into teams for a friendly game of soccer.
During the game, a wild kick sent the ship's captain running after the ball. When he picked it up his eyes fell upon a piece of rusty metal protruding from the sand.
Investigating further, he dug around the item until he recognized it as an old iron pot filled with coins. Just beyond site of the crew, he stuck the pot inside a rock crevice intending to keep the matter to himself and quietly return for it later.
Once the crew had returned to the ship, the captain made an excuse to remain for a short time. He returned to what he thought was the very crevice he'd stashed the pot in, but it wasn't there.
He searched briefly, stunned that he hadn't immediately found the pot, then decided to let the crew in on his find.
With the entire company now searching the various fissures, rocks and crevices in the immediate vicinity, the captain was certain of quick success. But hours passed without success and all returned to the ship disappointed to resume their trek.
Since there have been no reports of this cache being found at a later time, many believe it remains hidden among the rocks on Manana Island.Ragged Island (KNOX COUNTY) – No specific treasures are known to be buried on Ragged Island, but the island's history makes it a probable site worth looking into. Because of this island's isolated location, it is known to have been a popular safe haven and rendezvous spot for various criminal enterprises for centuries.
Plus Ragged Island is the site where one of the few counterfeiting operations in Maine's history was headquartered for many years before being found out by federal agents.John's Island (HANCOCK COUNTY) – From her days of old when pirates roamed these waters, there was an old tavern that once sat on the north end of this tiny spit of land known as John's Island.
Local legend tells of a pirate's treasure said to lie at the bottom of a hidden well here, and of a dead man's treasure map showing the exact location of that well.
Legend speaks of a Portuguese sailor who frequented the old tavern regularly, a known hangout for seafarers of every kind. He was a curious fellow who was known to crew onboard pirate ships and was always loaded with plenty of gold and silver to spend every time he stopped in at the tavern.
The Portuguese stood out because he didn't seem to be part of any crew for any particular ship, nor did he move in a group with his fellow shipmates, and he never worked. This went on for years unquestioned, until he died while at sea. Before he passed he called a shipmate to his bedside and passed him a piece of paper. It was a map of John's Island showing the location of a hidden well.
He told his shipmate at the bottom of the well… "was more gold and silver than half a dozen men could carry away." Adding, "I know because I helped put it there." Soon after he was dead.
What the shipmate did from there is unknown, but the site of the well remains unknown to this day and no reports of any recoveries have ever been made.Bailey Island (CUMBERLAND COUNTY) – Legend claims Captain Kidd buried a large cache of treasure here. Resident John Wilson was living on the island in 1853 and set out to find Kidd's treasure. Wilson dug up a copper kettle buried deep. Inside he found $12,000 in Spanish gold coins, but the cache is not thought to be part of Kidd's treasure.Monroe Island (WALDO COUNTY) – Monroe Island is reputed to have been used for numerous criminal enterprises dating back to the time of the early pirates. Smugglers and rumrunners later used the island for many years.
In 1884, the sidewheel steamer City of Portland wrecked on the island where survivors are reported to have buried personal caches of gold and silver coins after coming on shore.The Lost Stanwood Mummies
YORK COUNTY – Back in 1855, in order to alleviate a critical shortage of rags, Augustus Stanwood purchased a number of Egyptian mummies at .03 cents per pound.
Stanwood brought them to the U.S. and stored them in a cave on his property. How many he bought is unknown, but the cave is said to have been "full" of them.
Once the paper-rag shortage passed the mummies were no longer of use and Stanwood forgot about them.
Over time the entrance to the cave became lost. As far as anyone knows it has never been found. The cave of mummies is on the old property once owned by Stanwood that is located about 10 miles southwest of Portland near the county line. Local research is necessary.Lost Silver Mine
(CUMBERLAND COUNTY) – Early settlers of the village of Cornish learned that the local Indians were working a secret silver mine somewhere near the confluence of the Saco River and the Ossippi River. For quite some time the settlers tried to find the location of this mine, but failed. As far as I know the mine remains lost to this day.Diamonds Hidden on the Ridge
(AROOSTOOK COUNTY) – During the 1850's, it was common knowledge among those living along the northeastern boarder that quantities of diamonds were being smuggled into the United States from Canada.
Legend claims a man whose name is not known one day appeared from the woods near Buffalo alone.
While speaking to the locals in Buffalo, he stated his daughter and he were traveling and intended to board a ship at Bangor to complete the rest of their journey. But his daughter had died on the ridge overlooking Portage Lake where he had buried her.
At the top of that ridge, known as Carpenter Ridge he said he'd also buried a pouch filled with diamonds worth $250,000.
He resumed his trek without returning for the diamonds, perhaps thinking it best that the cache was safer where it was, but surprisingly was never seen in the area again.
The gravesite was discovered in 1975 and a search commenced for the diamond cache, without success.
It is thought to remain buried near the summit of Carpenter Ridge.Sources:
Island Treasures research:
Henson, Michael Paul, Legendary Pirate Treasure Sites Dot Maine Coastline, September 1981, Lost Treasure, p. 48 – 50
Terry, Thomas P., U.S. Treasure Atlas, 1985, La Crosse, WI, Specialty Publishing Company, p. 463, 468 – 470.