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

Our plain-English summary of Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1, by K.E. Hwang, Y.S. Kim, Y.R. Hwang, et al (Oncology Reports, 2015).

The study

• Authors: K.E. Hwang, Y.S. Kim, Y.R. Hwang, S.J. Kwon, D.S. Park, B.K. Cha, B.R. Kim, K.H. Yoon, E.T. Jeong, H.R. Kim
• Journal: Oncology Reports
• Published: 2015;33(5):2411-9
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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-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.

In plain English

This was a laboratory study by researchers in the Republic of Korea. It used two human cancer cell lines grown in dishes, not patients: the mesothelioma cell line MSTO-211H and the lung adenocarcinoma cell line A549. The authors treated the cells with pemetrexed, a chemotherapy drug used for malignant mesothelioma and non-small cell lung cancer, mostly at 2 µM for 24 hours, to study how it kills cancer cells. Pemetrexed reduced cell survival in a dose-dependent manner and increased apoptosis (programmed cell death) in both cell lines. It raised levels of reactive oxygen species (ROS), caused signs of mitochondrial damage, and lowered levels of the protein SIRT1. Pretreatment with the antioxidant N-acetylcysteine reduced these effects. Blocking SIRT1 increased pemetrexed-induced cell death. Resveratrol, a SIRT1 activator, reduced it. Pemetrexed produced 22.5% (MSTO-211) and 26.8% (A549) more apoptotic cells than untreated cells, and resveratrol lowered this by 16.0% and 18.1%. The authors concluded that pemetrexed killed these cells through mitochondrial damage mainly dependent on ROS build-up and lower SIRT1.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory experiment on human cancer cell lines (in vitro)
• Who was studied: Two human cancer cell lines: the mesothelioma cell line MSTO-211H (from the American Type Culture Collection) and the lung adenocarcinoma cell line A549 (from the Korean Cell Line Bank); study by authors at Wonkwang University and Chonbuk National University, Republic of Korea
• Exposure: The chemotherapy drug pemetrexed (various concentrations for viability tests; 2 µM for 24 h in most experiments), alone or combined with N-acetylcysteine (10 mM), SIRT1-blocking siRNA, or resveratrol (10 µM). No asbestos exposure was studied.
• Main results:
  • Pemetrexed reduced the growth of MSTO-211 and A549 cells in a dose-dependent manner
  • Pemetrexed increased apoptosis in MSTO-211 and A549 cells
  • Pemetrexed raised reactive oxygen species levels in both cell lines by 24 hours after treatment
  • Pemetrexed was associated with release of cytochrome c from the mitochondria into the rest of the cell, a sign of mitochondrial damage
  • SIRT1 protein levels fell with longer treatment time and higher pemetrexed dose
  • Pretreatment with the antioxidant N-acetylcysteine (NAC) reduced the pemetrexed-induced increase in apoptotic cells in both cell lines
  • Combining SIRT1-blocking siRNA with pemetrexed increased ROS generation more than either alone in both cell lines
  • The authors interpreted the siRNA experiments as showing that lowering SIRT1 enhanced pemetrexed-induced apoptosis
  • Pemetrexed produced 22.5% (MSTO-211) and 26.8% (A549) more apoptotic cells than untreated cells
  • Resveratrol, a SIRT1 activator, decreased the number of apoptotic cells after pemetrexed treatment by 16.0% (MSTO-211) and 18.1% (A549)
• The authors' conclusion: The authors concluded that pemetrexed induced apoptosis in the mesothelioma and A549 lung cancer cells through mitochondrial dysfunction, mainly dependent on ROS accumulation and SIRT1 downregulation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Apoptosis, Malignant Mesothelioma, Lung Cancer, Reactive Oxygen Species (ROS), Antifolate, Non-Small Cell Lung Cancer, A549 Cells.

Related studies

• Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction — K.E. Hwang, Y.S. Kim, et al. (2014)
• Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species — M. Tanaka, Y. Miura, et al. (2015)
• Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis — C.B. Lim, C.M. Prêle, et al. (2015)
• Licochalcone A induces apoptosis in malignant pleural mesothelioma through downregulation of Sp1 and subsequent activation of mitochondria-related apoptotic pathway — K.H. Kim, G. Yoon, et al. (2015)
• Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells — L. Su, G. Liu, et al. (2011)
• Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway — K.H. Kim, J.I. Chae, et al. (2016)

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