Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells.
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.
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea.
Ki-Eun
KE
Hwang
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea.
Young-Suk
YS
Kim
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea.
Jae-Wan
JW
Jung
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea.
Su-Jin
SJ
Kwon
Department of Laboratory Medicine, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea.
Do-Sim
DS
Park
Department of Thoracic and Cardiovascular Surgery, Chonbuk National University Medical School, Jeonju, Jeonbuk, Korea.
Byong-Ki
BK
Cha
Department of Natural Medical Sciences, College of Health Science, Chosun University, Seosuk-dong, Gwangju, Korea.
Seon-Hee
SH
Oh
Department of Radiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, Korea.
Kwon-Ha
KH
Yoon
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea.
Eun-Taik
ET
Jeong
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea.
Hak-Ryul
HR
Kim
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology*; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D000068437:Pemetrexed / Q000494:pharmacology*; D010436:Pepstatins / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D010436:Pepstatins; D047428:Protein Kinase Inhibitors; D000068437:Pemetrexed; C057620:bafilomycin A; C025946:3-methyladenine; D019821:Simvastatin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000225:Adenine; C031375:pepstatin
apoptosis; autophagy; pemetrexed; simvastatin