Tumor control of
hepatocellular carcinoma by
radiotherapy remains unsatisfactory. The
phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a critical role in inhibiting
cancer cell death. Elevated PI3K/Akt activity is associated with increased cellular resistance to irradiation. Our aim was to determine whether the inhibition of PI3K/Akt activity by a PI3K inhibitor,
BKM120, contributes to the increased sensitivity of
liver cancer cells to irradiation. The
hepatocellular carcinoma cell lines (Huh7 and BNL) were used to evaluate the in vitro synergism between
BKM120 and irradiation. Balb/c mice bearing ectopic BNL xenografts were treated with
BKM120 and/or
radiotherapy to assess the in vivo response.
BKM120 increased cell killing by radiation, increased the expression of apoptotic markers, and suppressed the repair of radiation-induced
DNA double-strand breaks.
BKM120 pretreatment inhibited radiation-induced Akt phosphorylation and enhanced the
tumor-suppressive effect and radiation-induced
tumor cell apoptosis in ectopic xenografts. Inhibition of mTOR phosphorylation by
rapamycin enhanced the radiosensitivity of BKM120-treated
hepatocellular carcinoma cells. The synergism between
BKM120 and irradiation likely inhibits the activation of Akt by radiation, leading to increased cell apoptosis and suppression of
DNA-double-strand breaks repair in
hepatocellular carcinoma cells. These data suggest that the
BKM120/radiation combination may be a strategy worthy of clinical trials.