title: ABT-737, a Bcl-2 Selective Inhibitor, and Chloroquine Synergistically Kill Renal Cancer Cells.
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.
authors.affiliation: Department of Nephrology, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Yin
authors.forename: Jinpeng
authors.initials: J
authors.lastname: Jia
authors.forename: Jijun
authors.initials: J
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.forename: Yiyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fengkun
authors.initials: F
authors.lastname: Chen
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001713:Biphenyl Compounds / Q000008:administration & dosage; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000008:administration & dosage; D004357:Drug Synergism; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D009596:Nitrophenols / Q000008:administration & dosage; D009842:Oligopeptides / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: C448308:2-(3-chloropropionylamino)-1,3,4-thiadiazole-5-sulfonamide; C501332:ABT-737; D000590:Amino Acid Chloromethyl Ketones; D051017:Apoptosis Regulatory Proteins; D001713:Biphenyl Compounds; D009596:Nitrophenols; D009842:Oligopeptides; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D013830:Thiadiazoles; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D002738:Chloroquine; D007930:Leucine; C024974:E 64