Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells

• Published in: Oncotarget Vol. 6; no. 30; pp. 29482 - 29496
• Main Authors: Hwang, Ki-Eun, Kim, Young-Suk, Jung, Jae-Wan, Kwon, Su-Jin, Park, Do-Sim, Cha, Byong-Ki, Oh, Seon-Hee, Yoon, Kwon-Ha, Jeong, Eun-Taik, Kim, Hak-Ryul
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 06.10.2015
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - metabolism; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Autophagy-Related Protein 5; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Synergism; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Macrolides - pharmacology; Mesothelioma - drug therapy; Mesothelioma - metabolism; Mesothelioma - pathology; Mesothelioma, Malignant; Mice, Nude; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Pemetrexed - pharmacology; Pepstatins - pharmacology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; RNA Interference; Signal Transduction - drug effects; Simvastatin - pharmacology; Time Factors; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Transfection; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; simvastatin; apoptosis; pemetrexed; autophagy
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5022

Pemetrexed, a multitarget antifolate used to treat malignant mesothelioma and non-small cell lung cancer (NSCLC), has been shown to stimulate autophagy. In this study, we determined whether autophagy could be induced by pemetrexed and simvastatin cotreatment in malignant mesothelioma and NSCLC cells. Furthermore, we determined whether inhibition of autophagy drives apoptosis in malignant mesothelioma and NSCLC cells. Malignant mesothelioma MSTO-211H and A549 NSCLC cells were treated with pemetrexed and simvastatin alone and in combination to evaluate their effect on autophagy and apoptosis. Cotreatment with pemetrexed and simvastatin induced greater caspase-dependent apoptosis and autophagy than either drug alone in malignant mesothelioma and NSCLC cells. 3-Methyladenine (3-MA), ATG5 siRNA, bafilomycin A, and E64D/pepstatin A enhanced the apoptotic potential of pemetrexed and simvastatin, whereas rapamycin and LY294002 attenuated their induction of caspase-dependent apoptosis. Our data indicate that pemetrexed and simvastatin cotreatment augmented apoptosis and autophagy in malignant mesothelioma and NSCLC cells. Inhibition of pemetrexed and simvastatin-induced autophagy was shown to enhance apoptosis, suggesting that this could be a novel therapeutic strategy against malignant mesothelioma and NSCLC.