Biozentrum, University of Basel, 4056 Basel, Switzerland.
Basilea Pharmaceutica International Ltd., Basel, Switzerland.
Sci Adv. 2016 Dec 23;2(12):e1601756. doi: 10.1126/sciadv.1601756. eCollection 2016 Dec.
We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine's known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer.
我们报告称，广泛使用的糖尿病药物二甲双胍的抗癌活性被长春瑞滨强烈增强。两种药物联合使用产生的合成致死作用是协同的，并且仅对转化细胞起作用。这种效应与长春瑞滨作为囊泡单胺转运体抑制剂的已知作用无关。长春瑞滨在体外与糖酵解酶α-烯醇酶结合，γ-烯醇酶同工型的表达与对药物组合的不反应性相关。长春瑞滨使癌细胞对二甲双胍及其更有效的衍生物苯乙双胍（phenformin）产生敏感性，远远低于每种化合物的单独毒性阈值。因此，联合使用长春瑞滨和共药物是一种有前途的治疗策略，可用于临床应用治疗癌症。
