Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
J Cell Mol Med. 2013 Mar;17(3):377-85. doi: 10.1111/jcmm.12019. Epub 2013 Feb 7.
Inhibitors of PI3-K/Akt are currently being assessed clinically in patients with advanced RCC. Identification of therapeutic strategies that might enhance the efficacy of PI3-K/Akt inhibitors is therefore of great interest. As PI3-K inhibition would be expected to have many pro-apoptotic effects, we hypothesized that there may be unique synergy between PI3-K inhibitors and BH3-mimetics. Towards this end, we assessed the combination of the PI3K inhibitor LY 294002 and the Bcl-2 family inhibitor ABT-737 in RCC cell lines. We found that the combinatorial treatment with these agents led to a significant increase in PARP cleavage and cell death in all RCC cell lines. The synergized cell death was correlated with decreased levels of Mcl-1 and XIAP, and increased levels in Bim, and appears critically dependent upon the activation of caspase 3 and 8. The enhanced lethality observed with the combination also appears dependent upon the regulation of XIAP, Mcl-1 and Bim levels. Our results suggest that the combination of PI3-K inhibitors with BH3-mimetics may be a viable therapeutic strategy in RCC.
目前，PI3K/Akt 抑制剂正在晚期 RCC 患者中进行临床评估。因此，寻找可能增强 PI3K/Akt 抑制剂疗效的治疗策略具有重要意义。由于 PI3K 抑制预计会产生许多促凋亡作用，我们假设 PI3K 抑制剂和 BH3 模拟物之间可能存在独特的协同作用。为此，我们评估了 PI3K 抑制剂 LY 294002 和 Bcl-2 家族抑制剂 ABT-737 在肾细胞癌细胞系中的联合作用。我们发现，这些药物联合治疗导致所有肾癌细胞系中 PARP 切割和细胞死亡显著增加。协同细胞死亡与 Mcl-1 和 XIAP 水平降低以及 Bim 水平升高相关，并且似乎严重依赖于 caspase 3 和 8 的激活。观察到的组合增强的致死性似乎也依赖于 XIAP、Mcl-1 和 Bim 水平的调节。我们的研究结果表明，PI3K 抑制剂与 BH3 模拟物的联合应用可能是 RCC 的一种可行的治疗策略。
