title: MCL-1 is the key target of adjuvant chemotherapy to reverse the cisplatin-resistance in NSCLC.
abstract: Cisplatin is one of the most effective chemotherapeutic agents for the treatment of lung cancer. However, the acquired resistance occurred in cancer cells limits the clinical application of cisplatin. MCL-1, which is an important member in the pro-survival Bcl-2 family, plays a critical role in multidrug resistance (MDR). The aim of the present study is to investigate the value of Pan-Bcl-2 inhibitor as sensitizer for the chemotherapy of cisplatin-resistant non-small cell lung cancer (NSCLC) cells. We found the obatoclax but not the ABT-737 significantly decreased the IC50 (half maximal inhibitory concentration) of cisplatin in cisplatin-resistant NSCLC cells. Furthermore, we demonstrated that the mechanism of obatoclax-promoted cell death induced by cisplatin was dependent on the inhibition of MCL-1, which couldn't be inhibited by ABT-737 but is the target of obatoclax. Moreover, inhibition of MCL-1 recovered the function of NOXA and BAK in cisplatin-resistant NSCLC cells, leading to the promotion of mitochondrial apoptosis induced by cisplatin. Interestingly, our date indicated the obatoclax also reversed the cross-resistance in cisplatin-resistant NSCLC cells. Therefore, we demonstrated that the targeted therapy with MCL-1 inhibitors, such as obatoclax, may represent a novel strategy for cancer therapy.
authors.affiliation: Thoracic Surgery Department, 1st Affiliated Hospital of Sun Yat-Sen Univesity, Guangzhou 510080, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Pancreato-Biliary Surgery Department, 1st Affiliated Hospital of Sun Yat-Sen Univesity, Guangzhou 510080, China.
authors.forename: Zhenxian
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Colorectal Surgery Department, 1st Affiliated Hospital of Sun Yat-Sen Univesity, Guangzhou 510080, China.
authors.forename: Kaiming
authors.initials: K
authors.lastname: Wu
authors.affiliation: Division of Cardiac Surgery, 1st Affiliated Hospital of Sun Yat-Sen Univesity, Guangzhou 510080, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Anaesthesiology, 1st Affiliated Hospital of Sun Yat-Sen Univesity, Guangzhou 510080, China. Electronic address: guangzhoukzl@yeah.net.
authors.forename: Kuanzhi
authors.initials: K
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D006801:Humans; D007211:Indoles; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; D007211:Indoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D002945:Cisplatin; C520962:obatoclax
keywords: ABT-737; Chemoresistance; Cisplatin; MCL-1; NSCLC; Obatoclax