3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis.
OBJECTIVE
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.
Kusama
Toshiyuki
T
Department of Tumor Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan. kusama-to@mail.mc.pref.osaka.jp
Mukai
Mutsuko
M
Iwasaki
Teruo
T
Tatsuta
Masaharu
M
Matsumoto
Yoshirou
Y
Akedo
Hitoshi
H
Inoue
Masahiro
M
Nakamura
Hiroyuki
H
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000188:drug therapy; D007211:Indoles / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000556:secondary; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D004815:Epidermal Growth Factor; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D020742:rhoA GTP-Binding Protein