The effects of buthionine sulfoximine on the proliferation and apoptosis of biliary tract cancer cells induced by cisplatin and gemcitabine

Abstract

Patients with biliary tract cancer (BTC) have a poor prognosis. Advanced BTC patients have been treated with cisplatin in combination with gemcitabine, however, the treatment has had little impact on survival rates, and more effective treatments are urgently required for this disease. Previous studies discovered that buthionine sulfoximine (BSO), a potent inhibitor of glutathione (GSH) synthesis, was able to enhance the cytotoxic effect of various drugs in cancer cells. Phase I studies demonstrated that continuous-infusion of BSO was relatively non-toxic and resulted in the depletion of tumor GSH. However, the synergistic effect of BSO and cisplatin in BTC cells remains unknown, and no reports are available regarding sensitization to gemcitabine by BSO. In the present study, the effect of BSO in combination with cisplatin or gemcitabine in the treatment of BTC cells was examined in vitro. Cytotoxic effects were measured using an MTT assay, Annexin V assay and fluorescence-activated cell sorting analysis. Antiapoptotic protein expression levels were examined using western blot analysis. The results revealed that a sub-toxic concentration of BSO was capable of significantly enhancing cisplatin-induced apoptosis in BTC cells. The mechanisms of BSO's effect on BTC cells may be attributable to the reduction of GSH levels and downregulation of the expression of antiapoptotic proteins (Bcl-2, Bcl-xL and Mcl-1). Furthermore, BSO enhanced the antiproliferative effect of gemcitabine. In conclusion, the present data are the first results to indicate that BSO may sensitize BTC cells to standard first-line chemotherapeutic agents (cisplatin and gemcitabine). Combining BSO with cisplatin and gemcitabine is a promising therapeutic strategy for the treatment of BTC.