https://scholars.lib.ntu.edu.tw/handle/123456789/487324
標題: | Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells | 作者: | Chen K.-F. Chen H.-L. Tai W.-T. Feng W.-C. CHIH-HUNG HSU PEI-JER CHEN ANN-LII CHENG |
公開日期: | 2011 | 出版社: | American Society for Pharmacology and Experimental Therapy | 卷: | 337 | 期: | 1 | 起(迄)頁: | 155-161 | 來源出版物: | Journal of Pharmacology and Experimental Therapeutics | 摘要: | Hepatocellular carcinoma (HCC) is one of the most common potentially lethal human malignancies worldwide. Sorafenib, a tyrosine kinase inhibitor, was recently approved by the United States Food and Drug Administration for HCC. In this study, we established two sorafenib-resistant HCC cell lines from Huh7, a human HCC cell line, by long-term exposure of cells to sorafenib. Sorafenib induced significant apoptosis in Huh7 cells; however, Huh7-R1 and Huh7-R2 showed significant resistance to sorafenib-induced apoptosis at the clinical relevant concentrations (up to 10 μM). Thorough comparisons of the molecular changes between Huh7 and resistant cells showed that the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway played a significant role in mediating acquired resistance to sorafenib in Huh7-R1 and Huh7-R2 cells. Phospho-Akt and p85 (a regulatory subunit of PI3K) were up-regulated, whereas tumor suppressor phosphatase and tensin homolog were down-regulated in these resistant cells. In addition, ectopic expression of constitutive Akt in Huh7 demonstrated similar resistance to sorafenib. The knockdown of Akt by RNA interference reversed resistance to sorafenib in Huh7-R1 cells, indicating the importance of Akt in drug sensitivity. Furthermore, the combination of 8-[4-(1-aminocyclobutyl) phenyl]-9-phenyl-1,2,4-triazolo[3,4-f][1,6]naphthyridin-3(2H)-one dihydrochloride (MK-2206), a novel allosteric Akt inhibitor, and sorafenib restored the sensitivity of resistant cells to sorafenib-induced apoptosis. In conclusion, activation of PI3K/Akt signaling pathway mediates acquired resistance to sorafenib in HCC, and the combination of sorafenib and MK-2206, an Akt inhibitor, overcomes the resistance at clinical achievable concentrations. Copyright ? 2011 by The American Society for Pharmacology and Experimental Therapeutics. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984541581&doi=10.1124%2fjpet.110.175786&partnerID=40&md5=a785cf38e680fa9dd70c81ba8d51cc23 https://scholars.lib.ntu.edu.tw/handle/123456789/487324 |
ISSN: | 0022-3565 | DOI: | 10.1124/jpet.110.175786 | SDG/關鍵字: | 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h)one; mk 2206; phosphatidylinositol 3 kinase; protein kinase B; protein kinase B inhibitor; protein p85; sorafenib; unclassified drug; apoptosis; article; cancer cell; cancer cell culture; cancer resistance; down regulation; drug effect; drug exposure; drug potentiation; drug sensitivity; human; human cell; liver cell carcinoma; long term exposure; priority journal; protein expression; signal transduction; upregulation |
顯示於: | 腫瘤醫學研究所 |
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