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Reversal of P‐gp mediated multidrug resistance in‐vitro and in‐vivo by FG020318

Overexpression of P‐glycoprotein (P‐gp) by tumours results in multidrug resistance (MDR) to structurally and functionally unrelated chemotherapeutic drugs. Combined therapy with MDR‐related cytotoxins and MDR modulators is a promising strategy to overcome clinical MDR. This study was performed to explore the MDR reversal activity of a novel compound 2‐[4‐(2‐pyridin‐2‐yl‐vinyl) phenyl]‐4,5‐bis‐(4‐N,N‐diethylaminophenyl)‐1(H)‐imidazole (FG020318) in‐vitro and in‐vivo. Tetrazolium (MTT) assay was used to evaluate the ability of FG020318 to reverse drug resistance in two P‐gp‐expressing tumour cell lines, KBv200 and MCF‐7/adr. Intracellular doxorubicin accumulation was determined by fluorescence spectrophotometry in MCF‐7/adr cell line. The effect of FG020318 on P‐gp function was demonstrated by rhodamine 123 (Rh123) accumulation in KBv200 cells. KBv200 cell xenograft models were established to study the in‐vivo effect of FG020318 on reversing MDR. FG020318 was not cytotoxic by itself against P‐gp expressing KBv200 cells and MCF‐7/adr cells and their parental drug‐sensitive KB cells and MCF‐7 cells. FG020318 could significantly increase the sensitivity of MDR cells to antitumour drugs including doxorubicin and vincristine in MCF‐7/adr cells and KBv200 cells, respectively. It was much stronger than the positive control verapamil in reversal of MDR. FG020318 also increased the intracellular accumulation of doxorubicin in a concentration‐dependent manner in MCF‐7/adr cells, but did not affect the accumulation of doxorubicin in drug‐sensitive MCF‐7 cells. The Rh123 accumulation in resistant KBv200 cells was also increased by the addition of FG020318, but Rh123 accumulation was not affected by FG020318 in drug‐sensitive KB cells. FG020318 potentiated the antitumour activity of vincristine to KBv200 xenografts and was an efficacious modulator in‐vivo. Our results suggested that FG020318 was a highly potent, efficacious MDR modulator not only in‐vitro but also in‐vivo. The reversal of drug resistance by FG020318 was probably related to the increased anticancer drug accumulation and its inhibition of P‐gp function of MDR tumour cells.