Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1.
Pemetrexed is a multitargeted antifolate used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). However, the mechanism by which pemetrexed induces apoptosis remains unclear. In the present study, we investigated the involvement of reactive oxygen species (ROS) and sirtuin 1 (SIRT1) in pemetrexed-induced apoptosis in MSTO-211 malignant mesothelioma cells and A549 NSCLC cells. Pemetrexed enhanced caspase-dependent apoptosis, induced intracellular ROS generation, and downregulated SIRT1 in the MSTO-211 and A549 cells. Pemetrexed-induced apoptosis, which was prevented by pretreatment with N-acetyl-cysteine (NAC), was mediated by effects on the mitochondria, including mitochondrial membrane potential transition (MPT) and cytosolic release of cytochrome c, and also involved regulation of SIRT1 expression. Interference with SIRT1 expression using siRNA enhanced pemetrexed-induced apoptosis through mitochondrial dysfunction and ROS generation, whereas resveratrol, an activator of SIRT1, protected against pemetrexed-induced apoptosis. These results show that pemetrexed induces apoptosis in MSTO-211 mesothelioma cells and A549 NSCLC cells through mitochondrial dysfunction mediated by ROS accumulation and SIRT1 downregulation.
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea.
Ki-Eun
KE
Hwang
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea.
Young-Suk
YS
Kim
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea.
Yu-Ri
YR
Hwang
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea.
Su-Jin
SJ
Kwon
Department of Laboratory Medicine, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea.
Do-Sim
DS
Park
Thoracic and Cardiovascular Surgery, Chonbuk National University Medical School, Jeonbuk 570-749, Republic of Korea.
Byong-Ki
BK
Cha
Department of Obstetrics and Gynecology, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea.
Byoung-Ryun
BR
Kim
Department of Radiology, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea.
Kwon-Ha
KH
Yoon
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea.
Eun-Taik
ET
Jeong
Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea.
Hak-Ryul
HR
Kim
D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000068437:Pemetrexed / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D056564:Sirtuin 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D000068437:Pemetrexed; D045304:Cytochromes c; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000111:Acetylcysteine