The Mevalonate Synthesis Pathway as a Therapeutic Target in Cancer

Andela Valentine B., Pirri Michael, Schwarz Edward M. et al. The Mevalonate Synthesis Pathway as a Therapeutic Target in Cancer. Clinical Orthopaedics and Related Research. 2003;415(Suppl):S59-S66. doi:10.1097/01.blo.0000093846.72468.66.

Abstract

Farnesyl transferase inhibitors have emerged as bona fide anticancer agents whereas the development of geranylgeranyl transferase inhibitors has been mitigated by overt systemic toxicities. Evidence suggests that the therapeutic value of farnesyl transferase inhibitors is an indirect result of perturbations in the function of geranylgeranylated Rho proteins. To address this question, we used inhibitors of the mevalonate synthesis pathway to decrease cellular levels of farnesly and geranylgeranly isoprenoids and supplemented our culture systems with exogenous isoprenoids accordingly. Using a murine lung alveolar carcinoma cell line (Line 1), we report a dose-dependent inhibition of tumor cell proliferation, adhesion and invasiveness, in response to alendronate (3-30 micro mol/L) and mevastatin (1-10 micro mol/L). Supplementation of cultures with geranylgeranyl pyrophosphates (100 micro mol/L) was observed to rescue drug-induced phenotypic changes whereas farnesyl pyrophosphate (100 micro mol/L) had a minimal effect. Our observations highlight the mevalonate synthesis pathway as a target for anticancer therapies and suggest a greater role for geranylgeranylated proteins in cellular processes germane to cancer.

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