Abstract 4137: Verification of antitumor effect of γ-secretase-inhibitor and radiotherapy

[Background and Aim] Notch3 is a member of the Notch signaling pathway, which plays an important role in cancer development. We have already demonstrated that Notch3 is over-expressed in approximately 40% of lung cancer tumors and that inhibition of the Notch3 pathway by γ-secretase-inhibitor (GSI) induces apoptosis and suppresses tumor growth in lung cancer. Although a previous report has shown that radiation enhanced Notch1 expression in breast cancer, little is known about the relationship between radiation and Notch pathway. In this study, we attempt to elucidate the combined effect of GSI and radiotherapy in lung cancer. [Results] We used two Notch3-expressing lung cancer cell lines (HCC2429 and H460). In a MTT proliferation assay and clonogenic assay, combination of GSI and radiation suppressed the growth of lung cancer cells and colony formations compared to GSI or radiation alone. We also showed that GSI down-regulates Notch3 expression in a dose dependent manner, and radiation up-regulates Notch expression and downstream Notch target gene, Hey-1. Notch up-regulation by radiation is down-regulated by the combination. Combination of GSI and radiation reduced p-Bcl2, Bcl-XL and p-Erk compared to GSI or radiation alone, whereas no effect on p-Akt level was seen.[Conclusion] Our results suggest that combination of GSI and radiation may be clinical potential strategy in the treatment of patients with lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4137.