MCL-1 is the key target of adjuvant chemotherapy to reverse the cisplatin-resistance in NSCLC

• Published in: Gene 2016-08, Vol.587 (2), p.147-154
• Main Authors: Ma, Jun, Zhao, Zhenxian, Wu, Kaiming, Xu, Zhe, Liu, Kuanzhi
• Format: Article
• Language: English
• Subjects: ABT-737; Antineoplastic Agents - pharmacology; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell Line, Tumor; Chemoresistance; Cisplatin; Cisplatin - pharmacology; Drug Resistance, Neoplasm; Drug Therapy, Combination; Humans; Inhibitory Concentration 50; Lung Neoplasms - drug therapy; MCL-1; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; NSCLC; Obatoclax; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrroles - pharmacology
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2016.04.054

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. •Obatoclax can reverse the cisplatin-resistance in NSCLC.•Obatoclax reverses the cisplatin-resistance by overcoming the overexpression of MCL-1 in CPR-A549.•Combination with obatoclax and cisplatin leads to the release of BAK and NOXA from MCL-1 in CPR-A549.•Obatoclax reverses the cisplatin-resistance via induction of mitochondrial apoptosis in CPR-A549.•Obatoclax reverses the cross-resistance of CPR-A549 to doxorubicin, TRAIL and 5-fluorouracil.