Abstract 3747: Pulsatilla saponin D suppresses angiogenesis and induces apoptosis via inhibition of PI3K/Akt/mTOR signaling pathway in hepatocellular carcinoma

Constitutive activation of PI3K/Akt/mTOR signaling pathway has been shown in hepatocellular carcinoma, which plays a central role in promoting survival, proliferation, and angiogenesis. Here, we assessed efficacy of Pulsatilla saponin D (designated SB365) on the progression of HCC and regulation of PI3K/Akt/mTOR signaling. SB365 strongly suppressed the growth of HCC cells in a dose-dependent manner. Also, SB365 induced apoptosis by increasing the proportion of sub-G1 apoptotic cells from 8% to 21% through induction of expression of Bax and cleaved-caspase-3. In vivo study showed that SB365 significantly inhibited tumor growth in HCC xenograft model, inducing apoptosis by increasing the expression of the cleaved caspase-3 and DNA fragmentation. In addition, SB365 showed a potent anti-angiogenic activity to decrease the expression of hypoxia-inducible factor-1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF) known as a key molecule for tumoric angiogenesis. Furthermore, SB365 suppressed tube formation and migration of HUVECs, and in vivo neovascularization in a mouse Matrigel plug assay as well. The expressions of VEGF and CD34 in the tumor tissue were decreased by SB365 treatment. In a mechanism study, we also found that SB365 effectively suppressed the phosphorylation of PI3K downstream factors such as Akt, mTOR, and p70S6K both in vitro and in vivo. Taken together, our study demonstrates that SB365 not only induces apoptosis but also inhibits cell growth/proliferation and angiogenesis through modulation of PI3K/Akt/mTOR pathway in human HCC. We suggest that SB365 may be a new chemotherapeutic candidate against HCC. Keywords: SB365; HCC; Apoptosis; Angiogenesis; PI3K 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 3747. doi:1538-7445.AM2012-3747