Open AccessSB 365 inhibits angiogenesis and induces apoptosis of hepatocellular carcinoma through modulation of PI 3 K / A kt/ mTOR signaling pathway
Author(s) -
Hong SangWon,
Jung Kyung Hee,
Lee HeeSeung,
Choi MyungJoo,
Son Mi Kwon,
Zheng HongMei,
Hong SoonSun
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2012.02409.x
Subject(s) - pi3k/akt/mtor pathway , angiogenesis , protein kinase b , cancer research , matrigel , apoptosis , vascular endothelial growth factor , chemistry , signal transduction , microbiology and biotechnology , biology , biochemistry , vegf receptors
Identification of small molecules that safely inhibit cancer progression is critical for cancer therapeutics. Saponins exhibit cytostatic and cytotoxic activity against various cancer cells, but the mechanism is not well understood. Here, we investigated whether saponin D (designated SB 365), an active component isolated from P ulsatilla koreana , could inhibit the progression of hepatocellular carcinoma ( HCC ) and considered its mechanism. SB 365 strongly suppressed the growth of HCC cells in a dose‐dependent manner and induced apoptosis by increasing the proportion of sub G 1 apoptotic cells from 8% to 21% through induction of expression of B ax and cleaved caspase‐3. In addition, SB 365 exhibited potent anti‐angiogenic activity and decreased the expression of hypoxia‐inducible factor‐1α ( HIF ‐1α) and vascular endothelial growth factor, a key molecule for angiogenesis. Furthermore, SB 365 suppressed the tube formation and migration of HUVEC , as well as in vivo neovascularization in a mouse Matrigel plug assay. In vivo study showed that SB 365 significantly inhibited tumor growth in an HCC xenograft model, inducing apoptosis by increasing the expression of the cleaved caspase‐3 and DNA fragmentation. The expressions of vascular endothelial growth factor and CD 34 in the tumor tissue were decreased by SB 365 treatment. In examining its mechanism, SB 365 was found to effectively suppress the phosphorylation of PI 3 K downstream factors, such as A kt, mTOR and p70S6 K both in vitro and in vivo . Our study demonstrates that SB 365 not only induces apoptosis but also inhibits cell growth and angiogenesis through modulation of the PI 3 K / A kt/ mTOR pathway in human HCC . We suggest that SB 365 may be a new chemotherapeutic candidate against HCC .