Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer.
Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors - HMG-CoA reductase inhibitors) have been approved for the treatment of lipid disorders. Recently, in vivo studies with experimental animals and in vitro studies indicated a possible role for statins in the treatment of malignancies. Inhibition of the enzyme HMG-CoA reductase results in decreased farnesylation and geranylgeranylation of several proteins essential for cellular proliferation and survival. Inhibition of Ras farnesylation was originally thought to be the mechanism that mediates statin-induced effects in cancer. Consequently, specific inhibitors of the enzyme farnesyltransferase (FTIs) were developed. Currently, the mechanisms that mediate statin- and FTI-induced antitumour effects are questioned. It remains unclear which proteins and signal transduction cascades are involved. This review focuses on the effects and possible therapeutic application of statins and FTIs. Antitumour properties such as induction of growth arrest and apoptosis, inhibition of metastasis and inhibition of angiogenesis are discussed. Furthermore, the mechanisms of statin- and farnesyltransferase inhibitor-induced effects and the involvement of a number of cellular components (such as farnesylated and geranylgeranylated proteins, the mitogen-activated protein kinase signalling pathway, the phosphoinositide 3'-kinase signalling pathway, and cell cycle regulatory proteins) are reviewed. In addition, clinical and epidemiological data with respect to statins and farnesyltransferase inhibitors are summarised. We propose that inhibitors of the mevalonate pathway are particularly effective when administered in combination with other drugs. Therefore, the mechanisms and effects of combined therapy of statins or farnesyltransferase inhibitors with chemotherapeutics, biphosphonates, non-steroidal anti-inflammatory drugs, specific inhibitors of geranylgeranyltransferase and inhibitors of tyrosine kinase activity are discussed.
Graaf
Matthijs R
MR
Department of Clinical Pharmacy, Academic Medical Centre Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. m.r.graaf@amc.uva.nl
Richel
Dick J
DJ
van Noorden
Cornelis J F
CJ
Guchelaar
Henk-Jan
HJ
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D009385:Neoplastic Processes; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase