Related Experiment Videos
Lovastatin induces apoptosis in malignant mesothelioma cells
J B Rubins1, T Greatens, R A Kratzke
1Department of Medicine, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, USA. rubin004@tc.umn.edu
Abstract:
Malignant mesothelioma causes profound morbidity and nearly universal mortality that is refractory to conventional treatment with aggressive surgery, radiotherapy, or chemotherapy. We report that pharmacologic concentrations of lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, induced apoptosis in human malignant mesothelioma cell lines. Mesothelioma cell viability was decreased in a dose-dependent manner by lovastatin (5 to 30 microM). These effects were not reversed by exogenous growth factors or cholesterol, but were reversed by addition of 100 microM mevalonate, confirming that lovastatin affected mesothelioma viability by inhibiting mevalonate synthesis. Lovastatin appeared to decrease mesothelioma viability by inducing apoptosis, as indicated by morphologic changes, histologic evidence of nuclear condensation and degeneration, and flow-cytometric analysis of DNA content. Lovastatin's effects on cell viability were partially reversed in the presence of farnesol, and treatment of mesothelioma cells with a specific farnesyl-protein transferase (FTP) inhibitor decreased cell viability and induced morphologic changes indistinguishable from those caused by lovastatin. In addition, lovastatin-treated cells showed translocation of ras guanosine triphosphate (GTP)-binding proteins from membrane to cytosolic fractions on Western blots, suggesting that lovastatin's effects on mesothelioma were mediated in part by disrupting acylation of GTP-binding proteins. Thus, lovastatin is a commercially available and clinically well-tolerated agent that reduces viability and induces apoptosis of mesothelioma cells, and may provide the basis for adjunctive treatments of patients with mesothelioma.
Insights
Lovastatin, a cholesterol-lowering drug, induces programmed cell death (apoptosis) in malignant mesothelioma cells by inhibiting mevalonate synthesis. This finding suggests lovastatin as a potential adjunctive treatment for mesothelioma.
Area of Science:
- Oncology
- Biochemistry
Background:
- Malignant mesothelioma is a rare but aggressive cancer with poor prognosis.
- Conventional treatments including surgery, radiotherapy, and chemotherapy are often ineffective.
Purpose of the Study:
- To investigate the effect of lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, on human malignant mesothelioma cell lines.
- To explore the mechanism by which lovastatin affects mesothelioma cell viability.
Main Methods:
- Treatment of mesothelioma cell lines with varying concentrations of lovastatin.
- Assessment of cell viability, apoptosis markers (morphology, DNA content), and protein acylation.
- Reversal studies using mevalonate, growth factors, cholesterol, and farnesol.
Main Results:
- Lovastatin significantly decreased mesothelioma cell viability in a dose-dependent manner.
- Lovastatin induced apoptosis, confirmed by morphological and flow-cytometric analyses.
- The effects were mediated by inhibition of mevalonate synthesis and partially by disrupting GTP-binding protein acylation.
Conclusions:
- Lovastatin effectively reduces viability and induces apoptosis in malignant mesothelioma cells.
- Lovastatin's mechanism involves inhibiting mevalonate synthesis and protein acylation.
- Lovastatin shows promise as an adjunctive therapy for mesothelioma patients.