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

// Ki-Eun Hwang 1, * , Young-Suk Kim 1, * , Jae-Wan Jung 1 , Su-Jin Kwon 1 , Do-Sim Park 2 , Byong-Ki Cha 3 , Seon-Hee Oh 4 , Kwon-Ha Yoon 5 , Eun-Taik Jeong 1 , Hak-Ryul Kim 1 1 Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea 2 Department of Laboratory Medicine, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea 3 Department of Thoracic and Cardiovascular Surgery, Chonbuk National University Medical School, Jeonju, Jeonbuk, Korea 4 Department of Natural Medical Sciences, College of Health Science, Chosun University, Seosuk-dong, Gwangju, Korea 5 Department of Radiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, Korea * These authors have contributed equally to this work Correspondence to: Hak-Ryul Kim, e-mail: kshryj@wku.ac.kr Keywords: autophagy, apoptosis, pemetrexed, simvastatin Received: March 30, 2015 Accepted: August 10, 2015 Published: August 20, 2015 ABSTRACT 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.