Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells.
The new combination between the nucleoside analogue gemcitabine and the cholesterol-lowering drug fluvastatin was investigated in vitro and in vivo on the human pancreatic tumour cell line MIAPaCa-2. The present study demonstrates that fluvastatin inhibits proliferation, induces apoptosis in pancreatic cancer cells harbouring a p21ras mutation at codon 12 and synergistically potentiates the cytotoxic effect of gemcitabine. The pharmacologic activities of fluvastatin are prevented by administration of mevalonic acid, suggesting that the shown inhibition of geranyl-geranylation and farnesylation of cellular proteins, including p21rhoA and p21ras, plays a major role in its anticancer effect. Fluvastatin treatment also indirectly inhibits the phosphorylation of p42ERK2/mitogen-activated protein kinase, the cellular effector of ras and other signal transduction peptides. Moreover, fluvastatin administration significantly increases the expression of the deoxycytidine kinase, the enzyme required for the activation of gemcitabine, and simultaneously reduces the 5'-nucleotidase, responsible for deactivation of gemcitabine, suggesting a possible additional role of these enzymes in the enhanced cytotoxic activity of gemcitabine. Finally, a significant in vivo antitumour effect on MIAPaCa-2 xenografts was observed with the simultaneous combination of fluvastatin and gemcitabine, resulting in an almost complete suppression and a marked delay in relapse of tumour growth. In conclusion, the combination of fluvastatin and gemcitabine is an effective cytotoxic, proapoptotic treatment in vitro and in vivo against MIAPaCa-2 cells by a mechanism of action mediated, at least in part, by the inhibition of p21ras and rhoA prenylation. The obtained experimental findings might constitute the basis for a novel translational research in humans.
Bocci
G
G
Division of Pharmacology and Chemotherapy, University of Pisa, Via Roma, I-56126 Pisa, Italy.
Fioravanti
A
A
Orlandi
P
P
Bernardini
N
N
Collecchi
P
P
Del Tacca
M
M
Danesi
R
R
D015720:5'-Nucleotidase / Q000187:drug effects; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000187:drug effects; D004357:Drug Synergism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000187:drug effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D003841:Deoxycytidine; D000077340:Fluvastatin; D003842:Deoxycytidine Kinase; D019950:Mitogen-Activated Protein Kinase 1; D015720:5'-Nucleotidase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020741:rho GTP-Binding Proteins; D008798:Mevalonic Acid; D000093542:Gemcitabine