Institute of Human Genetics, University Medical Center, Goettingen, Germany.
PLoS One. 2012;7(12):e52898. doi: 10.1371/journal.pone.0052898. Epub 2012 Dec 31.
We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.
我们寻找一种能够使肉瘤细胞对阿霉素（DOX）敏感的药物。我们报告称，双重 PI3K/mTOR 抑制剂 PI103 增强了几种肉瘤细胞系中 DOX 的疗效，并与 DOX 协同诱导细胞凋亡。PI103 降低了 MDR1 和 MRP1 的表达，导致 DOX 蓄积。然而，DOX 诱导的细胞凋亡增强与 DOX 蓄积无关。它也不涉及 mTOR 的抑制。相反，DOX 加 PI103 的联合治疗激活了 Bax、线粒体凋亡途径和 caspase 3。在裸鼠肉瘤细胞的异种移植物中，当 DOX 与特异性 PI3K 抑制剂 GDC-0941 联合使用时，也观察到 caspase 3 的激活。尽管与 GDC-0941 单独有效抑制肿瘤生长相比，凋亡增加并没有进一步影响肿瘤生长，但这些发现表明抑制 PI3K 可能改善肉瘤中 DOX 诱导的促凋亡作用。与最近关于神经母细胞瘤和胶质母细胞瘤衍生细胞的类似研究相结合，PI3K 抑制似乎是一种更普遍的选择，可使肿瘤细胞对蒽环类药物敏感。
