Abstract 4531: Anticancer potential of curcurbitacin IIa trough STAT3/JAK2-independent, survivin and PARP mediated apoptosis and disruption of actin cytoskeleton

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The medicinal plant Hemsleya amalils Diels has been used as a homeopathic treatment for various diseases in China for centuries and has recently been indicated as being effective in inhibiting cancer cell growth. To investigate the molecular mechanisms underlying the anti-cancer activity of Hemsleya family, we purified the active component curcurbitacin IIa. Curcurbitacin IIa inhibited cell growth, induced apoptosis in several cancer cell lines, and reduced tumor growth in vivo. Immunofluorescent light microscopy as well as time-lapse imaging demonstrated the remarkable clustering of filamentous actin and the increases in G2/M populations in cell cycle, indicating the disruption of mitosis as the potential mechanism of inducing apoptosis by curcurbitacin IIa. Flowcytometry confirmed increased cell death while western blots showed reduced phospho-histone H3 immunoreactivity, consistent with reduced mitosis. Cleavage of Poly (ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as a result of caspase activation, was increased dramatically while AKT phosphorylation and the Inhibitor of Apoptosis Protein survivin expression were reduced. Prostate cancer cells stably transfected with oncoprotein δ-catenin in which survivin expression was increased showed reduced efficacy of curcurbitacin IIa to induce cell death. Combined with lack of its effects on STAT3/JAK2 phosphorylation, theses studies highlight curcurbitacin IIa as a new class of anti-cancer drugs in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo apoptosis through inhibition of surviving, AKT, and PARP. Supported by Department of Defense (PC040569) and National Cancer Institute (CA111891). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4531.