Abstract 613: Synergistic antiproliferative activity of combined administration of atorvastatin and zoledronic acid in LNCaP and PC3 prostate cancer cells

Abstract

Abstract Atorvastatin (ATO) and other statins demonstrate anti-inflammatory, anti-proliferative, and pro-apoptotic activities that suggest possible utility in cancer chemoprevention. Bisphosphonates such as zoledronic acid (ZOL) are used clinically to manage bone metastases from prostate and other cancers, and also demonstrate anti-apoptotic and growth inhibitory effects on cancer cells. Should these agents demonstrate significant chemopreventive activity in preclinical cancer models, their desirable clinical safety profiles would make them high priority candidates for clinical evaluation as chemopreventive agents. The present studies were performed to characterize the effects of ATO and ZOL on the in vitro proliferation kinetics of parental LNCaP and PC3 human prostate cancer cells, and in sub-clones of LNCaP and PC3 cells that differ phenotypically from the parental cell lines. When administered as single agents, ATO and ZOL both inhibited the proliferation of parental LNCaP cells and LNCaP cell sub-clones in a dose-dependent (1 - 20 µM) and time-dependent manner. Administration of ATO and ZOL in combination at concentrations at which each agent was minimally active as a single agent resulted in synergistic antiproliferative activity in both LNCaP cells and LNCaP sub-clones. For example, at 5 µM, ATO and ZOL each inhibited LNCaP cell proliferation by 5 to 10%; combined administration of ATO + ZOL at 5 µM inhibited LNCaP cell proliferation by nearly 50%. PC3 cells and sub-clones were also sensitive to statin administration: exposure of parental PC3 cells to ATO (5 µM) for 6 days induced significant cell death. ZOL inhibited proliferation in both PC3 cells and PC3 sub-clone cells in a dose and time-dependent manner; enhanced antiproliferative activity was seen in cells exposed to ATO + ZOL in combination. Because the autophagosomal marker, LC3-II, is reported to be induced by ATO in PC3 cells; LC3-II expression was evaluated in parental LNCaP cells and in PC3 cells by immunoblotting. ATO consistently induced LC3-II expression in PC3 cells, but had minimal effect on LC3-II expression in LNCaP cells. ZOL did not induce LC3-II expression in either cell line. Exposure to ATO + ZOL in combination induced LC3-II expression in PC3 cells only. These data demonstrate synergistic antiproliferative effects of ATO + ZOL in both LNCaP prostate cancer cells and PC3 prostate cancer cells, as well as in sub-clones derived from both prostate cancer cell lines. Enhanced chemotherapeutic and/or chemopreventive efficacy may be achieved in prostate cancer cells by administration of drug combinations that act through different molecular mechanisms. (N01-CN-43303 from the NCI, DHHS). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 613. doi:1538-7445.AM2012-613