Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction

Our plain-English summary of Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction, by K.E. Hwang, Y.S. Kim, Y.R. Hwang, et al (International Journal of Oncology, 2014).

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: International Journal of Oncology
• Published: 2014;45(4):1769-77
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pemetrexed is a multitarget antifolate currently used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors used primarily for hyperlidpidemia, have been studied for their antiproliferative and pro-apoptotic effects. However, the effects of simvastatin on pemetrexed-induced apoptosis have not been investigated. In this study, we investigated whether combination treatment with pemetrexed and simvastatin potentiates the apoptotic activity above that is seen with either drug alone in malignant mesothelioma and NSCLC cells. We found that the combination of pemetrexed and simvastatin induced more extensive caspase-dependent apoptosis than either drug alone in malignant mesothelioma cells (MSTO-211) or NSCLC cells (A549). In addition, reactive oxygen species (ROS) generation in cells treated with both pemetrexed and simvastatin was markedly increased compared to cells treated with either pemetrexed or simvastatin alone. Combination treatment also increased the loss of mitochondrial membrane potential, increased cytosolic release of cytochrome c, and altered expression of inhibitor of apoptosis proteins (IAP) and B-cell lymphoma-2 (Bcl-2) families of apoptosis related proteins. On the other hand, pretreatment with N-acetylcysteine (NAC) prevented apoptosis and mitochondrial dysfunction by pemetrexed and simvastatin. In addition, Bim siRNA conferred protection against apoptosis induced by pemetrexed and simvastatin. These results suggest that combination of pemetrexed and simvastatin potentiates their apoptotic activity beyond that of either drug alone in malignant mesothelioma and lung cancer cells. This activity is mediated through ROS-dependent mitochondrial dysfunction and Bim induction.

In plain English

This was a laboratory study of cancer cells grown in dishes, not of patients or animals. The cells were MSTO-211 malignant mesothelioma cells and A549 human lung cancer cells. The authors treated them with the chemotherapy drug pemetrexed (1 µM), the cholesterol-lowering drug simvastatin (5 µM), or both. In both cell lines, the authors reported that the combination had a synergistic effect in slowing cell growth. It also significantly increased apoptosis (programmed cell death) compared with either drug alone. The combination raised levels of reactive oxygen species (chemically reactive molecules), caused signs of mitochondrial dysfunction, and changed levels of proteins that control cell death, including an increase in Bim. Pretreating cells with the antioxidant N-acetylcysteine reduced these effects. Reducing Bim with a gene-silencing method reduced apoptosis-related proteins, which the authors took to mean Bim contributed at least in part. The authors concluded that the combination may be a clinically promising therapy for malignant mesothelioma or non-small cell lung cancer. They added that further studies, including animal models, are required before human studies.

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 (in vitro) cell culture experiment testing a drug combination and its mechanism
• Who was studied: Two human cancer cell lines: MSTO-211 malignant mesothelioma cells (from the American Type Culture Collection) and A549 lung cancer cells (from the Korean Cell Line Bank); the work was done at Korean universities
• Exposure: Pemetrexed (1 µM) and/or simvastatin (5 µM), typically for 48 hours; some experiments added the antioxidant N-acetylcysteine (10 mM) or Bim siRNA. No asbestos exposure was studied.
• Main results:
  • In both MSTO-211 and A549 cells, the combination had a synergistic inhibitory effect on cell growth
  • In both cell lines, the combination significantly increased apoptosis compared with either drug alone
  • In both cell lines, reactive oxygen species rose markedly with the combination compared with either drug alone
  • The combination increased loss of mitochondrial membrane potential and release of cytochrome c into the cell fluid
  • The combination lowered the anti-apoptotic proteins Mcl-1 and Bcl-xL and raised the pro-apoptotic proteins Bim and Puma; XIAP and survivin were significantly decreased relative to either drug alone
  • Pretreatment with N-acetylcysteine abolished the increase in reactive oxygen species caused by the combination
  • Pretreatment with N-acetylcysteine markedly reduced the increase in apoptotic cells caused by the combination
  • Silencing Bim with siRNA reduced expression of apoptosis-related proteins
• The authors' conclusion: The authors concluded that the combination may be a clinically promising therapy for malignant mesothelioma or NSCLC. They stated that its effects were mediated through ROS-triggered mitochondrial dysfunction and Bim induction.
• Limitations the authors state:
  • The findings come from cell lines only; the authors state that animal (xenograft) studies are needed before human studies

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: Apoptosis, Pemetrexed (Alimta), Malignant Mesothelioma, Lung Cancer, Reactive Oxygen Species (ROS), Antifolate, Non-Small Cell Lung Cancer.

Related studies

• Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1 — K.E. Hwang, Y.S. Kim, 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)
• Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression — D. Barbone, P. Cheung, et al. (2012)
• Modulation of reactive oxygen species via ERK and STAT3 dependent signalling are involved in the response of mesothelioma cells to exemestane — B. Nuvoli, E. Camera, et al. (2018)
• COX-2 specific inhibitors enhance the cytotoxic effects of pemetrexed in mesothelioma cell lines — S.L. O'Kane, G.L. Eagle, et al. (2010)
• Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species — M. Tanaka, Y. Miura, et al. (2015)

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