Comparative effects of lovastatin on mammary and prostate oncogenesis in transgenic mouse models

Abstract

The effects of lovastatin, a potent inhibitor of HMG CoA reductase, on experimental mammary and prostate oncogenesis, were studied in vitro and in vivo. Lovastatin inhibited cell growth in vitro in a dose-dependent manner for both mammary and prostate cancer cell lines, which was associated with p53-independent apoptosis. Flow cytometric analyses of lovastatin-treated mammary and prostate cancer cells demonstrated cell-cycle G(1) arrest, as well as decreases in S and G(2)/M fractions. p21(Waf1) and p27(Kip1) were induced by lovastatin in both types of cancer cells. Gene expression profiling of cells treated with lovastatin, however, was remarkable for a paucity of transcriptional changes induced by lovastatin. Treatment with lovastatin for 4 weeks did inhibit the formation of pre-neoplastic mammary intraepithelial neoplasias (MIN) in vivo, but not invasive carcinomas in the C3(1)/SV40 TAg transgenic model of mammary cancer. The decreased multiplicity of MIN lesions was associated with increased levels of apoptosis in these lesions. However, cell proliferation in the mammary lesions was not significantly different between lovastatin-treated and control mice 1 day after lovastatin treatment. In female mice treated with lovastatin for 12 weeks, there was a tendency for reduced tumor volume, which did not reach statistical significance. However, lovastatin did not suppress any lesion formation in the prostate of C3(1)/SV40 TAg transgenic male mice. Our results suggest that as lovastatin exerts an inhibitory effect on the development of early mammary lesions of mammary carcinogenesis, this compound may be useful for the chemoprevention of mammary cancer and might have utility as an adjuvant in breast cancer therapy. The chemopreventive effects of lovastatin in vivo, however, may be tissue-specific.

Statin-mediated reduction of osteopontin expression induces apoptosis and cell growth arrest in ovarian clear cell carcinoma

“…In general, various cancers are sensitive to statin treatment (33)(34)(35). Similarly, ovarian cancer cells may be sensitive to simvastatin treatment (12).…”

“…In addition, statins induce apoptosis through both the extrinsic and intrinsic pathways. Shibata et al (34) reported that lovastatin induced p53-independent mitochondrial-mediated apoptosis in a mouse mammary carcinoma. The sensitivity of different cell types to statin-induced apoptosis varies; acute myeloid leukemic and neuroblastoma cells are more sensitive than acute lymphoblastic leukemic cells (40).…”

Recombinant p21 Protein Inhibits Lymphocyte Proliferation and Transcription Factors

“…The indirect approach can be through the agents capable of inducing the expression of cyclin inhibitors or via peptides mimicking the effects of these inhibitors. In a number of studies, the indirect effect of cyclin inhibitor p21 has been demonstrated, either overexpression via viral and nonviral vectors (1)(2)(3)(4)(5)(6) or through the induction of p21 by different therapeutic agents (7)(8)(9)(10). We have demonstrated previously that anti-inflammatory/immunosuppressive drugs, e.g., cyclosporine (CsA) 2 , tacrolimus (TAC), and sirolimus (SRL) (11)(12)(13), induce the expression of cyclin inhibitor p21.…”

Lovastatin induces G1-phase synchronization of HEC-1-A cells and JEC cells

“…Wu et al applied 5 μmol/L lovastatin to treat CHO cells for 32 hours and the proportion of cells in G1 phase was 90% (Wu and Gilbert, 2000). In addition, lovastatin at 10 and 20 μmol/L was applied to treat M6 cells and MCF-1 cells for 24 and 33 hours, respectively, and 78% and 77~96% of cells were identified to be in the G1 phase (Gupta et al, 2003;Shibata et al, 2003). Treatment of Pr14 cells and Pc-3M cells with 10 μmol/L lovastatin for 24 hours and 24~48 hours can achieve 82% and 68~90% of cells in G1 phase, respectively (Park et al, 2001;Shibata et al, 2003).…”

“…In addition, lovastatin at 10 and 20 μmol/L was applied to treat M6 cells and MCF-1 cells for 24 and 33 hours, respectively, and 78% and 77~96% of cells were identified to be in the G1 phase (Gupta et al, 2003;Shibata et al, 2003). Treatment of Pr14 cells and Pc-3M cells with 10 μmol/L lovastatin for 24 hours and 24~48 hours can achieve 82% and 68~90% of cells in G1 phase, respectively (Park et al, 2001;Shibata et al, 2003). Treatment of T-24 cells with 30 μmol/L lovastatin may achieve 80% of cells in G1 phase and about 70~90% of Calu-1 cells were identified to be in the G1 phase following treatment with 30 μmol/L lovastatin (Jakobisiak et al, 1991;Vogt et al, 1997).…”