Med Sci Monit. 2017 Mar 29;23:1507-1513.
Synergistic Cytotoxicity of β-Elemene and Cisplatin in Gingival Squamous Cell Carcinoma by Inhibition of STAT3 Signaling Pathway.
Department of Dentistry, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).
Department of Radiotherapy, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China (mainland).
BACKGROUND Cisplatin remains one of the most active agents and is the mainstay of combination chemotherapy regimens against gingival squamous cell carcinoma. However, the efficacy of cisplatin is limited by its high toxicity and the development of drug resistance. β-elemene, isolated from the Chinese herb Rhizoma zedoariahas, is highly effective against malignancies and has low toxicity, but the development of β-elemene sensitizing chemotherapy in targeting the STAT3 signaling pathway remains unexplored in gingival squamous cell carcinoma. The present study was conducted to assess the chemosensitizing effects of b-elemene for enhancing the cytotoxicity of cisplatin in gingival squamous cell carcinoma. MATERIAL AND METHODS The gingival squamous cell carcinoma YD-38 cell line was used. MTT assay, clonogenic assay, annexin V/PI apoptosis assay, Western blot analysis, and xenograft model treatment were carried out in vitro and in vivo. RESULTS β-elemene significantly enhanced proliferative inhibition and cisplatin induced apoptosis in gingival squamous cell carcinoma. Cisplatin combined with β-elemene decreased the expressions of p-STAT3, p-JAK2, and Bcl-2, and increased the expressions of Bax and caspase-3 significantly compared to cisplatin only treatment, as well as in the xenograft model. CONCLUSIONS The results indicated that β-elemene promoted the anti-proliferative and apoptotic effect of cisplatin by inhibiting STAT3 and blocking the JAK2-STAT3 signaling pathway in GSCC in vitro and in vivo.
Anti-proliferative effect of β-elemene with increasing concentrations in GSCC cell line YD-38.
β-elemene promoted cisplatin sensitivity in GSCC cell line YD-38 with increasing doses. * Statistically significant difference between the cisplatin+β-elemene groups and the cisplatin treatment only group (P<0.01, by ANOVA). # No statistically significant difference between the low dose and high dose of β-elemene with cisplatin (P>0.05, by t-test).
Low dose of β-elemene promoted cytotoxicity of cisplatin in a dose-dependent manner in GSCC cell line YD-38, as determined by clonogenic assay. * Statistically significant difference between the cisplatin+β-elemene groups and the cisplatin treatment only group (P<0.01, by t-test).
β-elemene promoted cisplatin-induced apoptosis in GSCC cell line YD-38. * Statistically significant difference between the cisplatin+β-elemene groups and the cisplatin treatment only group (P<0.01, by t-test).
β-elemene enhanced cisplatin-induced protein expressions of STAT3, JAK2, Caspase-3, Bcl-2, and Bax on GSCC cell line YD-38. Cisplatin combined with β-elemene decreased the expressions of p-STAT3, p-JAK2, and Bcl-2, and increased the expressions of Bax and caspase-3 significantly compared to the cisplatin group, as determined by Western blotting analysis.
β-elemene promotes cisplatin sensitivity on tumor volumes and weight of mice in a YD-38 xenograft mouse model. * Statistically significant difference between the cisplatin+β-elemene groups and the cisplatin treatment only group (P<0.01, by t-test).
β-elemene enhanced cisplatin-induced protein expressions of STAT3, JAK2, caspase-3, Bcl-2, and Bax in tumor tissues. Cisplatin combined with β-elemene decreased the expressions of p-STAT3, p-JAK2, and Bcl-2, and increased the expressions of Bax and caspase-3 significantly compared to the cisplatin group, as determined by Western blotting analysis.