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  • Title: Zoledronic acid increases docetaxel cytotoxicity through pMEK and Mcl-1 inhibition in a hormone-sensitive prostate carcinoma cell line.
    Author: Fabbri F, Brigliadori G, Carloni S, Ulivi P, Vannini I, Tesei A, Silvestrini R, Amadori D, Zoli W.
    Journal: J Transl Med; 2008 Aug 08; 6():43. PubMed ID: 18691406.
    Abstract:
    BACKGROUND: In prostate cancer, the identification of drug combinations that could reduce the tumor cell population and rapidly eradicate hormone-resistant cells potentially present would be a remarkable breakthrough in the treatment of this disease. METHODS: The study was performed on a hormone-sensitive prostate cancer cell line (LNCaP) grown in normal or hormone-deprived charcoal-stripped (c.s.) medium. Cell viability and apoptosis were assessed by SRB assay and Annexin-V/TUNEL assays, respectively. Activated caspase-3, p21, pMEK and MCL-1 expression levels were detected by western blotting. RESULTS: The simultaneous exposure of zoledronic acid [100 microM] and docetaxel [0.01 microM] for 1 h followed by treatment with zoledronic acid for 72, 96 or 120 h produced a high synergistic interaction (R index = 5.1) with a strong decrease in cell viability. This cytotoxic effect was associated with a high induction of apoptosis in both LNCaP and in c.s. LNCaP cells. The induction of apoptosis was paralleled by a decrease in pMEK and Mcl-1 expression. CONCLUSION: The zoledronic acid-docetaxel combination produced a highly significant synergistic effect on the LNCaP cell line grown in normal or hormone-deprived medium, the principal molecular mechanisms involved being apoptosis and decreased pMEK and Mcl-1 expression. This experimentally derived schedule would seem to prevent the selection and amplification of hormone-resistant cell clones and could thus be potentially used alongside standard androgen deprivation therapy in the management of hormone-sensitive prostate carcinoma.
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