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 p21(WAF1/CIP1), and immunohistochemical staining for p21(WAF1/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.