Research

Zoledronic acid increases docetaxel cytotoxicity through pMEK and Mcl-1 inhibition in a hormone-sensitive prostate carcinoma cell line

Francesco Fabbri¹ , Giovanni Brigliadori¹ , Silvia Carloni¹ , Paola Ulivi¹ , Ivan Vannini¹ , Anna Tesei¹ , Rosella Silvestrini¹ , Dino Amadori² and Wainer Zoli¹

¹Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Italy

²Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Italy

author email corresponding author email

Journal of Translational Medicine 2008, 6:43doi:10.1186/1479-5876-6-43

Published:	8 August 2008

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 μM] and docetaxel [0.01 μM] 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.