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Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma

 Wonwoo KIM  ;  Jinsil SEONG  ;  Hae Jin OH  ;  Jung Hee AN 
 JOURNAL OF RADIATION RESEARCH, Vol.48(3) : 187-195, 2007 
Journal Title
Issue Date
Androstadienes/administration & dosage* ; Animals ; Apoptosis/drug effects* ; Apoptosis/radiation effects* ; Carcinoma, Hepatocellular/pathology* ; Carcinoma, Hepatocellular/radiotherapy* ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; Liver Neoplasms/pathology* ; Liver Neoplasms/radiotherapy* ; Male ; Mice ; Mice, Inbred C3H ; Radiation Dosage ; Radiation Tolerance/drug effects ; Radiation-Sensitizing Agents/administration & dosage ; Wortmannin
The objective of this study was to explore whether a specific inhibitor of PI3K, wortmannin, could potentiate the antitumor effect of radiation in vivo, particularly on radioresistant murine tumors. C3H/HeJ mice bearing syngeneic hepatocarcinoma (HCa-I) were treated with 25 Gy radiation, wortmannin, or both. Wortmannin was administered intraperitoneally (1 mg/kg) once daily for 14 days. Tumor response to treatment was determined by a tumor growth delay assay. Possible mechanisms of action were explored by examining the level of apoptosis and regulating molecules. The expression of regulating molecules was analyzed by Western blot for p53 and p21WAF1/CIP1, and immunohistochemical staining for p21WAF1/CIP1, CD31 and VEGF. In the tumor growth delay assay, wortmannin increased the effect of tumor radioresponse with an enhancement factor (EF) of 2.00. The level of apoptosis achieved by the combined treatments was shown to be no more than an additive effect; peak apoptotic index was 11% in radiation alone, 13% in wortmannin alone, and 19% in the combination group. Markedly increased areas of necrosis at 24 h in the combination group were noted. Western blotting showed upregulation of p21WAF1/CIP1 in the combination treatment group, which correlated with low levels of VEGF. Microvascular density was evidently also reduced, based on low expression of CD31. In murine hepatocarcinoma, the antitumor effect of radiation was potentiated by wortmannin. The mechanism seems to involve not only the increase of induced apoptosis but also enhanced vascular injury. Wortmannin, in combination with radiation therapy, may have potential benefits in cancer treatment.
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1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Kim, Won Woo(김원우)
Seong, Jin Sil(성진실) ORCID logo https://orcid.org/0000-0003-1794-5951
Oh, Hae Jin(오해진)
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