PO-198 Flavopereirine suppresses colorectal cancer growth via inducing cell cycle arrest and apoptosis in P53 signalling dependence

High-grade colorectal cancer (CRC) worldwide is a significant cause of morbidity and mortality. However, the benefit of present therapies are actually limited. Flavopereirine, an alkaloid isolated from Geissospermum vellosii, is shown to suppress the viability of various cancer cells through unknown action. Presently, we investigated the functional mechanism and therapeutic potential of flavopereirine on CRC cells in in vitro and in vivo. Effects of flavopereirine on the viability, cell cycle, and apoptosis were evaluated in various CRC cell lines in in vitro, using cell proliferation reagent WST-1, propidium iodide staining, and propidium iodide plus annexin-V double staining, respectively. Protein profiles in cell cycle and apoptosis regulation were verified by Western blotting. Furthermore, CRC cells with p53 null or p53 loss-of-function mutation were applied to investigate the mechanism of flavopereirine-mediated growth inhibition. Moreover, the therapeutic efficacy of flavopereirine on the growth of CRC xenograft mouse model was examined in in vivo. Expressions of P53 and P21 and stimulation of apoptosis by TUNEL staining were further determined in flavopereirine-treated CRC tissues by immunohistochemistry. Our data demonstrated that flavopereirine significantly suppressed viability, caused both intrinsic and extrinsic apoptosis, and induced G2/M-phase cell cycle arrest on CRC cells. On mechanismic study, flavopereirine declined the capacity to suppress the viability and to induce apoptosis in p53 null and p53 loss-of-function mutation CRC cells, indicating the important involvement of P53 activity on flavopereirine-medicated growth suppression. Moreover, flavopereirine significantly repressed the growth of CRC and was followed with the upregulation of P53 and P21 expressions and induction of TUNEL-positive apoptosis in tissues in vivo. This study indicates that the therapeutic effect of flavopereirine on suppressing the growth of CRCs is through inhibiting the viability, causing G2/M cell cycle arrest, and inducing apoptosis in the manner of P53 dependence, suggesting that flavopereirine might be a potential drug for treating CRC which carries active P53 expression.