Abstract C73: Anticancer effects of a novel phosphoinositol 3-kinase inhibitor in human hepatocellular carcinoma
Abstract The phosphatidylinositol 3-kinase (PI3K) is one of the most important regulators of cancer cell growth, survival, motility, and metabolism. As PI3K is activated in a wide variety of human malignancies, it is emerging as an attractive target for cancer treatment. Recently, we have designed a...
Saved in:
Published in | Molecular cancer therapeutics Vol. 10; no. 11_Supplement; p. C73 |
---|---|
Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
12.11.2011
|
Online Access | Get full text |
Cover
Loading…
Summary: | Abstract
The phosphatidylinositol 3-kinase (PI3K) is one of the most important regulators of cancer cell growth, survival, motility, and metabolism. As PI3K is activated in a wide variety of human malignancies, it is emerging as an attractive target for cancer treatment. Recently, we have designed and synthesized a new series of imidazo [1,2-a] pyridine derivatives as PI3Ka inhibitors. In this study, we investigated the effect of HS-196 [ethyl 6-(5-(2,4-difluorophenylsulfonamido) pyridin-3-yl) imidazo [1,2-a] pyridine-3-carboxylate] in human hepatocellular carcinoma (HCC) cells. HS-196 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt, mTOR, p70S6K and glycogen synthase kinase 3b (GSK3b) by western blotting and immunofluorescence staining. And HS-196 showed anti-proliferative effects in variety of HCC cells in a dose-dependent manner. Interestingly, HS-196 didn't affect the normal liver cell line (HL-7702), while sorafenib and doxorubicin showed cytotoxicity at the same concentration. Also, HS-196 induced apoptosis by increasing the proportion of sub-G1 apoptotic cells, and caused cell cycle arrest at G0/G1 phase. HS-196 increased the expression of p27 and p21 and decreased that of cyclin D1 associated with cell cycle arrest. The induction of apoptosis by HS-196 was confirmed by DAPI and TUNEL staining, and the increases of the cleaved PARP, caspase-3, caspase-9 were observed. Furthermore, HS-196 decreased the expression of hypoxia-inducible factor-1a(HIF-1a) and vascular endothelial growth factor (VEGF) and inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVECs), which were confirmed by Matrigel plug assay performed in BALB/c nude mouse. Taken together, these results demonstrated that HS-196 exhibited its anticancer activity through disrupting the PI3K/Akt pathway, causing cell cycle arrest and consequently inducing apoptosis, and inhibiting angiogenesis in human HCC cells. We suggest that HS-196 may be a potential new candidate for targeted HCC therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C73. |
---|---|
ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.TARG-11-C73 |