3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis

Background & Aims: Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase blocks the mevalonate metabolic pathway, which is necessary for the isoprenylation of a number of small guanosine triphosphatases. We examined the effects of HMG-CoA reductase inhibitors, fluvastatin and lovastatin, on human pancreatic cancer cell invasion in vitro and experimental liver metastasis in vivo. Methods: Cell invasion was studied in a modified Boyden chamber assay. The translocation of RhoA was assessed by immunoblotting. Experimental liver metastases were Induced in nude mice by intrasplenic inoculation of ASPC-1 human pancreatic cancer cells. Results. Fluvastatin and lovastatin inhibited the in vitro cancer cell invasion induced by epidermal growth factor (EGF) in a manner sensitive to C3 transferase, a specific inhibitor of Rho. Treatment of ASPC-1 cells with fluvastatin markedly attenuated the EGF-induced translocation of RhoA from the cytosol to the membrane fraction and caused cell rounding. The effects of fluvastatin could be reversed by the addition of all-trans-geranylgeraniol. Administration of fluvastatin to nude mice reduced both metastatic tumor formation in the liver and the growth of established liver metastases at doses recommended for the treatment of hypercholesterolemia in humans. Conclusions: HMG-CoA reductase inhibitors can be antimetastatic agents with the potential for useful clinical applications.