The major obstacle in radiotherapy or chemotherapy is the resistance of cancer cells to the therapies. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates antioxidant enzymes. Kelch-like ECH-associated protein (Keap1) sequesters Nrf2 and leads to proteasomal degradation of Nrf2 in non-stressed condition. Keap1 is often found with biallelic mutation in non-small cell lung cancer (NSCLC) cell lines and NSCLC patients, results in constitutive activation of Nrf2 function, and contributes to resistance to anticancer drugs. Therefore, we aimed to develop small molecules that inhibit Nrf2 activity to maximize radiation-induced cell death via increasing ROS generation. A cell-based high-throughput screening using luciferase assay, we have identified an aniline derivative (IM3829) as a radiosensitizer of lung cancer in vitro and in vivo. In clonogenic assay, this compound sensitized H1299 lung cancer cells to irradiation.

IM3829 with irradiation significantly increased ROS accumulation compared with radiation alone treated cells, leading to apoptotic cell death synergistically. IM3829 inhibited Nrf2 binding activity and HO-1 expression. In H1299 xenografts mice, IM3829 with radiation significantly inhibits tumor growth by 47 % and 27 % compared with vehicle or radiation alone treated animals, respectively. Our finding suggested that IM-3829 could be a promising radiosensitizer in lung cancer patients, particularly those with a high expression of Nrf2.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-369. doi:10.1158/1538-7445.AM2011-LB-369