Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1

Hwang,Ki-Eun; Kim,Young-Suk; Hwang,Yu-Ri; Kwon,Su-Jin; Park,Do-Sim; Cha,Byong‑Ki; Kim,Byoung-Ryun; Yoon,Kwon-Ha; Jeong,Eun-Taik; Kim,Hak-Ryul

doi:10.3892/or.2015.3830

Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1

Authors:
- Ki-Eun Hwang
- Young-Suk Kim
- Yu-Ri Hwang
- Su-Jin Kwon
- Do-Sim Park
- Byong‑Ki Cha
- Byoung-Ryun Kim
- Kwon-Ha Yoon
- Eun-Taik Jeong
- Hak-Ryul Kim
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Affiliations: Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea, Department of Laboratory Medicine, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea, Thoracic and Cardiovascular Surgery, Chonbuk National University Medical School, Jeonbuk 570-749, Republic of Korea, Department of Obstetrics and Gynecology, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea, Department of Radiology, Wonkwang University School of Medicine, Jeonbuk 570-749, Republic of Korea
Published online on: March 4, 2015 https://doi.org/10.3892/or.2015.3830
Pages: 2411-2419

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Abstract

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-acetylcysteine (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.

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