A disconnect between antitumor and antiangiogenic effects of fluvastatin in vitro and in vivo.
The possible role of statins in cancer is controversial. Indeed, among the multiplicity of biological effects ascribed to these widely used cholesterol lowering agents some could, at least in theory, inhibit tumor growth (e.g. by inhibiting Ras oncoproteins), while other actions are inert, or may even stimulate cancer aggressiveness (e.g. through promoting neovascularization). In order to address some of these controversies, we set out to compare the effects of statins on growth of cancer and endothelial cells in vitro, to the impact of these drugs on angiogenesis-dependent expansion of the corresponding tumors in vivo. Water-soluble fluvastatin was used at concentrations (0-800 ng/ml) against human umbilical vein endothelial cells (HUVEC), and several well-characterized cancer cell lines in culture, including: carcinoma (LLC), melanoma (B16F1) and fibrosarcoma driven by mutant H-ras (528ras1). Endpoints were based on 3H-thymidine incorporation assay, cell morphology and tumorigenicity in mice. The growth inhibitory effects of fluvastatin varied among cancer cell lines (LLC>B16F1>528ras1), irrespectively of their mutant H-ras status. Fluvastatin also blocked the action of angiogenic factors on cultured endothelial cells, but was relatively ineffective against highly angiogenic and aggressive tumors both in young mice (6-8 weeks), and in less aggressively growing tumors in aged (80-90 weeks) mice. Thus, antitumor and antiangiogenic activity of fluvastatin in vitro is not recapitulated in vivo. Tumors may display a form of resistance to statins through a mechanism operative only in vivo.
Klement
H
H
Henderson Research Centre, McMaster University, Hamilton, Canada. jrak@thrombosis.hhscr.org.
Rak
J
J
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009389:Neovascularization, Pathologic
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin