Journal
CANCER LETTERS
Volume 329, Issue 1, Pages 99-108Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2012.10.028
Keywords
PI3K; Anticancer; Apoptosis; Angiogenesis; HCC
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Funding
- Korean Health Technology R&D Project, Ministry of Health Welfare [A120266]
- National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology [NRF 2012-0002988, 2012 R1A2A2A01045602]
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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.
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