Induction of apoptosis and suppression of angiogenesis of hepatocellular carcinoma by HS-159, a novel phosphatidylinositol 3-kinase inhibitor

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The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer and is emerging as an attractive therapeutic target. In this study, we synthesized a novel PI3K alpha inhibitor, HS-159 [N-(5-(3-(3-cyanophenyl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide] and evaluated its anticancer effects on Huh-7 human hepatocellular carcinoma (HCC) cells. HS-159 effectively inhibited the phosphorylation of downstream PI3K effectors such as Akt, mTOR and P70S6 kinases in a dose-dependent manner. This compound also induced apoptosis and increased the fraction of apoptotic cells in the sub-G(1) phase as well as the levels of cleaved PARP, caspase-3 and -9. Furthermore, HS-159 decreased the expression of hypoxia inducible factor-1 alpha and vascular endothelial growth factor which play important roles in angiogenesis. The anti-angiogenic effect of HS-159 was confirmed by the suppression of tube formation and migration of human umbilical vein endothelial cells in vitro. Collectively, our results demonstrate that HS-159 exhibited anticancer activities including the induction of apoptosis and inhibition of angiogenesis by blocking the PI3K/Akt pathway in Huh-7 cells. Therefore, we suggest that this drug may be potentially used for targeted HCC therapy.
Publisher
SPANDIDOS PUBL LTD
Issue Date
2013-07
Language
English
Article Type
Article
Keywords

HYPOXIA-INDUCIBLE FACTOR-1; ENDOTHELIAL GROWTH-FACTOR; CANCER-THERAPY; ANTITUMOR-ACTIVITY; BREAST-CANCER; FACTOR-I; PATHWAY; TARGET; AKT; CELLS

Citation

INTERNATIONAL JOURNAL OF ONCOLOGY, v.43, no.1, pp.201 - 209

ISSN
1019-6439
DOI
10.3892/ijo.2013.1912
URI
http://hdl.handle.net/10203/175026
Appears in Collection
CH-Journal Papers(저널논문)
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