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Author Huang, Chao-Yuan ♦ Tai, Wei-Tien ♦ Wu, Szu-Yuan ♦ Shih, Chih-Ting ♦ Chen, Min-Hsuan ♦ Tsai, Ming-Hsien ♦ Kuo, Chiung-Wen ♦ Shiau, Chung-Wai ♦ Hung, Man-Hsin ♦ Chen, Kuen-Feng
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword RADIOLOGY AND NUCLEAR MEDICINE ♦ COMBINED THERAPY ♦ HEPATOMAS ♦ IN VITRO ♦ IN VIVO ♦ RADIOTHERAPY
Abstract Purpose: Hepatocellular carcinoma (HCC) is among the most lethal human malignancies, and curative therapy is not an option for most patients. There is growing interest in the potential benefit of combining targeted therapies with radiation therapy (RT). This study aimed to characterize the efficacy and mechanism of an investigational drug, dovitinib, used in combination with RT. Methods and Materials: HCC cell lines (PLC5, Hep3B, SK-Hep1, HA59T, and Huh-7) were treated with dovitinib, RT, or both, and apoptosis and signal transduction were analyzed. Results: Dovitinib treatment resulted in Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1)-mediated downregulation of p-STAT3 and promoted potent apoptosis of HCC cells. Ectopic expression of STAT3, or inhibition of SHP-1, diminished the effects of dovitinib on HCC cells. By ectopic expression and purified recombinant proteins of various mutant forms of SHP-1, the N-SH2 domain of SHP-1 was found to be required for dovitinib treatment. Overexpression of STAT3 or catalytic-dead mutant SHP-1 restored RT-induced reduction of HCC cell survival. Conversely, ectopic expression of SHP-1 or activation of SHP-1 by dovitinib enhanced the effects of RT against HCC in vitro and in vivo. Conclusions: SHP-1/STAT3 signaling is critically associated with the radiosensitivity of HCC cells. Combination therapy with RT and the SHP-1 agonist, such as dovitinib, resulted in enhanced in vitro and in vivo anti-HCC effects.
ISSN 03603016
Educational Use Research
Learning Resource Type Article
Publisher Date 2016-06-01
Publisher Place United States
Journal International Journal of Radiation Oncology, Biology and Physics
Volume Number 95
Issue Number 2


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