Lovastatin Induces Apoptosis in Malignant Mesothelioma Cells

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.

Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells

“…We and others have reported that the HMG-CoA reductase inhibitor lovastatin induces apoptosis of a variety of tumor cells including acute myelogenous leukemia, 9 medulloblastoma, 10 mesothelioma, 11 and neuroblastoma. 12 Recently, we have shown that lovastatin also induces significant apoptosis in a large number of tumor-derived cell lines including juvenile monomyelocytic leukemia, pediatric solid malignancies (rhabdomyosarcoma, medulloblastoma) and squamous cell carcinoma of the cervix and of the head and neck.…”

Synergistic induction of apoptosis by HMG-CoA reductase inhibitor and histone deacetylases inhibitor in HeLa cells

“…The HMG-CoA reductase inhibitors or statins, therefore, have pleiotropic biological and physiological effects on cell functions. Notably, statins have been shown to induce apoptosis in many cell lines [4][5][6][7][8][9][10][11].…”

“…Blockage of protein geranylgeranylation is believed to be the major mechanism for statin induction of apoptosis [4][5][6][7][8][9][10][11]. Therefore, targeting at protein geranylgeranylation could have an important role in anti-carcinogenesis [1,2,13].…”

Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis‐dependent mechanism

“…3 The isoprenylation of Ras proteins is critical for their cellular function and inhibition of isoprenylation abolishes the transforming activity of mutated Ras proteins. 4 Lovastatin, one of the statins that has also been found to arrest tumor and normal cells in G1 phase of the cell cycle, 5,6 induced a potent apoptotic response [7][8][9][10] and has been demonstrated to exert antitumor effects in mice. [11][12][13][14][15] In several studies using murine melanoma models, lovastatin was shown to have antitumor effects both when used alone 12 or in combination with other agents.…”