Targeting Phosphatidylinositide3-Kinase/Akt pathway by BKM120 for radiosensitization in hepatocellular carcinoma

Abstract

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.

Dual targeting of PI3K and MEK enhances the radiation response of K-RAS mutated non-small cell lung cancer

“…We first reported that activated Akt-mediated DNA damage repair can be suppressed by pharmacological or genetic targeting of Akt through the inhibition of DNA-PKcs [20–22]. Other reports also support our findings concerning the role of PI3K and/or Akt in DSBs repair and radioresistance [18, 19, 23–27]. …”

“…In this context, it could be demonstrated that activation of the PI3K/Akt pathway after exposure to ionizing radiation leads to efficient repair of DSBs through non-homologous end joining (NHEJ) as well as homologous recombination repair pathways [18, 19]. We first reported that activated Akt-mediated DNA damage repair can be suppressed by pharmacological or genetic targeting of Akt through the inhibition of DNA-PKcs [20–22].…”

Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling

“…There are numerous pathways involved in angiogenesis. For example, PI3K/AKT, PTEN/AKT, AKT/mTOR and mitogenactivated protein kinase kinase/ERK have all been associated with tumor angiogenesis via the upregulation of VEGF (33)(34)(35)(36). Previous studies have demonstrated that the VEGF/PI3K/AKT pathway is associated with Nogo-B-induced angiogenesis in primary human retinal ECs (37).…”

Radio Resistance Mechanisms of Cancers: An Overview and Future Perspectives

“…Combining cetuximab with RT achieved excellent local control with minimal toxicity in pancreatic cancer patients [12]. Furthermore, it has been demonstrated that the synergism between IR and a PI3K inhibitor BKM120 inhibits the activation of Akt by IR, leading to a reduction in DSB repair and promotion of cell apoptosis in hepato cellular carcinoma cells [13]. These findings suggest a new therapeutic strategy for radio sensitizing the PI3K/AKT inhibitor treatment.…”