IPD-196, a novel phosphatidylinositol 3-kinase inhibitor with potent anticancer activity against hepatocellular carcinoma

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As the activation of phosphatidylinositol 3-kinase (PI3K) is associated with a wide variety of human malignancies, it is emerging as an attractive target for cancer treatment. In this study we synthesized a novel PI3K alpha, inhibitor, IPD-196 [ethyl 6-(5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylate], and evaluated its anticancer effects on human hepatocellular carcinoma (HCC) cells. IPD-196 effectively inhibited the phosphorylation of downstream PI3K effectors such as Akt, mTOR, p70S6K, and 4E-BP1, and its antiproliferative effect was more potent than that of sorafenib or LY294002. It also induced cell cycle arrest at the G0/G1 phase as well as apoptosis by increasing the proportion of sub-G1 apoptotic cells, and the levels of cleaved PARP, caspase-3, and caspase-9. Furthermore, it decreased the expression of HIF-1 alpha and VEGF in Huh-7 cells, and inhibited tube formation and migration of human umbilical vein endothelial cells, which was confirmed by a Matrigel plug assay in mice. Taken together, IPD-196 exhibited its anticancer activity through disruption of the PI3K/Akt pathway that caused cell cycle arrest, apoptosis induction, and inhibition of angiogenesis in human HCC cells. We therefore suggest that IPD-196 may be a potential candidate drug for targeted HCC therapy. Crown Copyright (c) 2012 Published by Elsevier Ireland Ltd. All rights reserved.
Publisher
ELSEVIER IRELAND LTD
Issue Date
2013-02
Language
English
Article Type
Article
Keywords

HYPOXIA-INDUCIBLE FACTOR-1; CANCER-THERAPY; SIGNALING PATHWAYS; GROWTH-FACTOR; SELECTIVE INHIBITOR; CDK INHIBITORS; BREAST-CANCER; KINASE; MECHANISMS; EXPRESSION

Citation

CANCER LETTERS, v.329, no.1, pp.99 - 108

ISSN
0304-3835
DOI
10.1016/j.canlet.2012.10.028
URI
http://hdl.handle.net/10203/173929
Appears in Collection
CH-Journal Papers(저널논문)
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