PI3K inhibition potentiates Bcl‐2‐dependent apoptosis in renal carcinoma cells |
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| Authors: | Shudong Zhu Matthew B Cohen Jeffrey D Bjorge James W Mier Daniel C Cho |
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| Institution: | 1. Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, , Boston, MA, USA;2. School of Biological Science and Technology, State Key Laboratory of Medical Genetics, Central South University, , Changsha, China;3. Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Research Institute, , Calgary, Canada |
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| Abstract: | 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. |
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| Keywords: | PI3K Bcl‐2 apoptosis renal carcinoma cell
XIAP
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