Open Access

ARTICLE

ABT-737, a Bcl-2 Selective Inhibitor, and Chloroquine Synergistically Kill Renal Cancer Cells

Pei Yin^*1, Jinpeng Jia^†1, Jijun Li^*, Yan Song^*, Yiyan Zhang^*, Fengkun Chen^*

* Department of Nephrology, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China
† Department of Orthopaedics, General Hospital of Chinese People’s Liberation Army, Beijing, China
1 These authors provided equal contribution to this work.

Oncology Research 2016, 24(1), 65-72. https://doi.org/10.3727/096504016X14587366983838

Abstract

Renal cell carcinoma (RCC) is the most common malignancy in the kidney in the world, and the 5-year overall survival for patients remains poor due to the lack of effective treatment strategies. Although ABT-737, as a Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic reagent, apoptosis induced by ABT-737 is often blocked in several types of cancer cells. This study investigated whether the combination of the small-molecule BH3 mimetic ABT-737 and the lysosome inhibitor chloroquine was an effective strategy for treating renal cancer cells. We found that the combination of ABT-737 and chloroquine synergistically decreased cell viability when compared to treatment with either single reagent. Cell apoptosis induced by a combined treatment was markedly inhibited by the caspase inhibitors z-DEVD-FMK and z-VAD-FMK. It was also inhibited by cathepsin inhibitor E-64 and CTSI (cathepsin inhibitor), which suggested that apoptosis was dependent on the cascade of caspase activation and cathepsins released from lysosomes. Furthermore, we found that ABT-737 could increase the cell level of ROS, which triggers cathepsin-mediated cell death and augments the role of chloroquine in cell death. So the combination of ABT-737 and chloroquine was an effective strategy for the treatment of renal cancer cells, and this combined strategy may widen the therapeutic window of ABT-737 and chloroquine as well as enhance the clinical efficacy of synergistic drug combinations.

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