The cytostatic effects of lovastatin on ACC-MESO-1 cells

Our plain-English summary of The cytostatic effects of lovastatin on ACC-MESO-1 cells, by K. Asakura, Y. Izumi, M. Yamamoto, et al (The Journal of Surgical Research, 2011).

The study

• Authors: K. Asakura, Y. Izumi, M. Yamamoto, Y. Yamauchi, K. Kawai, A. Serizawa, T. Mizushima, M. Ohmura, M. Kawamura, M. Wakui, T. Adachi, M. Nakamura, M. Suematsu, H. Nomori
• Journal: The Journal of Surgical Research
• Published: 2011;170(2):e197-209
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma is known to be widely resistant to therapy, and new treatment strategies are needed. Statins are small molecules that suppress the production of multiple hydrophobic substrates in the mevalonate pathway. Although still controversial, statins may decrease the risk of certain cancers such as colon cancer, lung cancer, and prostate cancer. Since the evaluations of the direct effect of statins on malignant mesothelioma are still few, the present study was done to evaluate the effects of lovastatin on ACC-MESO-1 cells in vivo and to investigate the potential mechanisms involved in vitro.

Materials And Methods: The in vivo effect of lovastatin was evaluated using an NOD/SCID/γnull (NOG) mouse model of human malignant mesothelioma using ACC-MESO-1 cells. Lovastatin was also applied to ACC-MESO-1 cells in vitro and the effects were observed.

Results: Lovastatin administration reduced primary tumor and metastasis in the NOG mouse model of human malignant mesothelioma. In vitro studies showed that lovastatin administration induced cytostatic effects as per reduced cell viability and cell migration in ACC-MESO-1 cells. These effects were suggested to be dependent on autophagic changes rather than apoptosis. Furthermore, induction of autophagic changes by lovastatin in ACC-MESO-1 cells was independent of mTOR, and was considered to be dependent at least in part on Rac/phospholipase C/ inositol 1,4,5-triphosphate axis.

Conclusions: These results suggest that it may be possible to utilize statins, or other pharmacological agents that are known to induce mTOR-independent autophagy, as an adjunct to standard treatments in malignant mesothelioma.

Copyright © 2011 Elsevier Inc. All rights reserved.

In plain English

This laboratory and animal study tested the cholesterol-lowering drug lovastatin on ACC-MESO-1, a human malignant pleural mesothelioma cell line. It did not study asbestos exposure. The authors injected the cells into the left chest of immunodeficient (NOG) mice. Ten mice then received lovastatin (12.5 mg/kg three times weekly for 8 weeks) and 10 received the solvent DMSO alone. Lovastatin significantly reduced the amount of primary tumor on the injected side and of metastases in the right chest (P less than 0.01). In cell culture, lovastatin reduced cell viability and cell migration at 48 hours without apparent apoptosis (programmed cell death). The cells instead showed signs of autophagy, a process in which cells digest their own contents. Blocking autophagy significantly reversed the drop in viability and migration. Further tests suggested these changes were independent of mTOR and ran at least partly through a Rac/phospholipase C/IP3 pathway. The authors suggested that agents inducing mTOR-independent autophagy may be usable as an adjunct to standard treatment. They noted that their lovastatin dose exceeded cholesterol-lowering doses and that other mesothelioma cell lines need study.

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 study combining an animal experiment (human mesothelioma cells implanted in the chest of immunodeficient mice) with cell-culture experiments
• Who was studied: The ACC-MESO-1 human malignant pleural mesothelioma cell line (from the Riken Cell Bank, Japan), grown in culture and implanted into the left chest cavity of male NOD/SCID/γnull (NOG) immunodeficient mice: 10 lovastatin-treated and 10 DMSO-treated
• Exposure: Lovastatin (a statin), given to mice by injection into the abdomen at 12.5 mg/kg body weight three times a week for 8 weeks, compared with the solvent DMSO alone; also applied to cells in culture for 48 hours. No asbestos or fiber exposure was studied.
• Main results:
  • In the mice, lovastatin (n = 10) significantly reduced the amount of primary tumor (left chest) and of metastases (right chest) compared with DMSO alone (n = 10) at 8 weeks (P less than 0.01)
  • In cell culture, lovastatin significantly reduced cell viability (MTT assay, n = 6 per group) and cell migration (wounding assay, n = 5 per group) at 48 hours compared with DMSO (P less than 0.01)
  • Lovastatin did not induce apparent apoptosis in the cells, unlike hydrogen peroxide used as a positive control
  • Lovastatin-treated cells showed vacuole-like structures, presumably autophagosomes, on electron microscopy at 48 hours, and an increase in the autophagy marker LC3B-II that was reversed by the autophagy inhibitor 3MA
  • The reduction in cell viability caused by lovastatin was significantly reversed by co-administration of the autophagy inhibitor 3MA (n = 6 per group, P less than 0.01); the reduction in migration was also significantly reversed
  • In the mouse tumors, cells staining positive for the autophagy markers LC3A and Beclin1 were significantly increased by lovastatin in both primary and metastatic tumors (n = 3 per group, 15 fields, P less than 0.01)
  • Adding geranylgeranyl pyrophosphate (GGPP) reversed lovastatin's effects on cell viability, migration and autophagy; the authors noted in the discussion that GGPP did not completely restore cell migration
  • Lovastatin-induced autophagy appeared independent of Akt/mTOR: phosphorylated mTOR and 4EBP1 were not significantly affected, active Akt did not reverse the viability loss, and rapamycin did not affect viability
  • Lovastatin-induced autophagy was IP3 dependent: a cell-permeable form of IP3 (Bt-IP3) reversed it, myo-inositol did not, and lovastatin reduced the membrane localization of phospholipase C-b2
• The authors' conclusion: The authors concluded that lovastatin induced autophagic changes in ACC-MESO-1 cells both in the mice and in culture, at least in part through the Rac/phospholipase C/IP3 axis. They suggested that agents known to induce mTOR-independent autophagy may be utilized as an adjunct to standard cytotoxic treatments in malignant mesothelioma.
• Limitations the authors state:
  • The lovastatin dose used exceeded the clinical dose used to lower cholesterol
  • Only one mesothelioma cell line was studied; further studies in other mesothelioma lines are needed
  • No dose-response study was done
  • Only the phospholipase C isozyme PLC-b2 was examined; other isozymes may also have been altered

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Colorectal Cancer, Lung Cancer, Mesothelioma, Metastasis, Apoptosis.

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