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

Oncotarget
Ki-Eun HwangHak-Ryul Kim

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 coul...Continue Reading

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Citations

Jun 22, 2016·Antimicrobial Agents and Chemotherapy·Ling ZhangJichang Li
Oct 21, 2017·The Kaohsiung Journal of Medical Sciences·Teng ZhaoLi-Kuan Hu
Jul 3, 2019·British Journal of Pharmacology·Chong-Chao HsiehPo-Len Liu
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Jul 30, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Jaqueline Aparecida DuarteElaine Amaral Leite

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Methods Mentioned

BETA
transmission electron microscopy
confocal microscopy
transfection
FACS
xenografts
fluorescence-activated cell sorting
Protein Assay
electrophoresis
xenograft

Software Mentioned

VGStudio MAX
Cell Quest
Xelis

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