Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma

Wonwoo Kim, Jinsil Seong, Jung Hee An, Hae Jin Oh

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 p21 WAF1/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.

Original languageEnglish
Pages (from-to)187-195
Number of pages9
JournalJournal of radiation research
Volume48
Issue number3
DOIs
Publication statusPublished - 2007 Jun 13

Fingerprint

tumors
apoptosis
augmentation
radiation
Neoplasms
Radiation Effects
Apoptosis
Vascular Endothelial Growth Factor A
necrosis
Western Blotting
staining
inhibitors
Radiation Dosage
mice
molecules
radiation therapy
Inbred C3H Mouse
Vascular System Injuries
cancer
Therapeutics

All Science Journal Classification (ASJC) codes

  • Radiation
  • Radiology Nuclear Medicine and imaging
  • Health, Toxicology and Mutagenesis

Cite this

Kim, Wonwoo ; Seong, Jinsil ; An, Jung Hee ; Oh, Hae Jin. / Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma. In: Journal of radiation research. 2007 ; Vol. 48, No. 3. pp. 187-195.
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Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma. / Kim, Wonwoo; Seong, Jinsil; An, Jung Hee; Oh, Hae Jin.

In: Journal of radiation research, Vol. 48, No. 3, 13.06.2007, p. 187-195.

Research output: Contribution to journalArticle

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T1 - Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma

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AU - Seong, Jinsil

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N2 - 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 p21 WAF1/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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