Simultaneous treatment with camptothecin and valproic acid suppresses induction of Bcl-X-L and promotes apoptosis of MCF-7 breast cancer cells

作者：Arakawa Yasuhiro^*; Saito Shinobu; Yamada Hisashi; Aiba Keisuke

来源：Apoptosis, 2009, 14(9): 1076-1085.

DOI：10.1007/s10495-009-0384-0

• Camptothecin
• Valproic acid
• Histone deacetylase inhibitor
• Simultaneous treatment
• Bcl-X-L
• Apoptosis

Camptothecin derivatives have been widely used for chemotherapy in patients with various cancers, but intrinsic and acquired drug resistance is major drawback to be overcome. In the present study, we demonstrated that simultaneous treatment with camptothecin and valproic acid induced apoptosis of MCF-7 cells, whereas neither agent alone could efficiently induce apoptosis. This induction of apoptosis was associated with loss of the mitochondrial membrane potential and was caspase dependent. Further investigation showed that concurrent treatment modulated the expression of pro-apoptotic and anti-apoptotic genes. Bcl-X-L expression was induced in MCF-7 cells treated with camptothecin alone, but not in cells treated simultaneously with camptothecin and valproic acid. Ectopic overexpression of Bcl-X-L in MCF-7 cells completely suppressed the induction of apoptosis, even with simultaneous treatment. On the other hand, efficient induction of apoptosis was achieved by treatment with camptothecin and Bcl-X-L inactivation (using siRNA or BH3 mimetic). The cytotoxic effect of camptothecin combined with valproic acid was more than additive for MCF-7 cells. Taken together, our results suggest that simultaneous administration of camptothecin and valproic acid might be useful for anticancer therapy.

• 出版日期2009-9