Abstract 2495: The autophagy inducing drug carbamazepine is a radiation protector and mitigator

Abstract The role of autophagy in cellular response to radiation is controversial. Some investigators report that induction of autophagy increases radiosensitivity whereas others report that it confers radioresistance. Carbamazepine, traditionally used to treat mood disorders, epilepsy and trigeminal neuralgia, has recently been shown to induce autophagy. We hypothesized that carbamazepine would be radioprotective in vitro and in vivo by upregulating autophagy in cells and tissue after irradiation. In clonogenic assays of murine hematopoietic progenitor cells (32Dcl3), carbamazepine at 1, 10 and 100 uM for 1 hour prior to irradiation (0 – 8 Gy) increased the Do from 1.5 ± 0.1 to 2.1 ± 0.1 (p = 0.011), 2.3 ± 0.1 (p = 0.010), and 3.6 ± 0.7 (p = 0.003), respectively. Carbamazepine after irradiation increased the shoulder (ñ) on the survival curve from 1.4 ± 0.3 to 10.1 ± 4.2 (p = 0.011), 5.5 ± 1.7 (p = 0.018), or 3.6 ± 0.8 (p = 0.014), respectively. C57BL/6NHsd mice with intraperitoneal injection of carbamazepine (20 mg/kg) immediately before or after 9.25 Gy irradiation demonstrated increased survival (p = 0.008 and 0.005, respectively). JC1 stain and TUNEL assay revealed that carbamazepine had no effect on changes in mitochondria potential or apoptosis, respectively, following 5 or 10 Gy. Immunoblot for LC3 in 32Dcl3 cells 24 hours after irradiation revealed a 3.3x (5 Gy) and 6.2x (10 Gy) increase in LC3II/LC3I when cells were incubated in 50 uM carbamazepine. Cells irradiated in the absence of carbamazepine exhibited a 1.3x (5 Gy) and 1.8x (10 Gy) LC3II/LC3I increase, respectively. This data suggest that carbamazepine may be a valuable radiation mitigator by upregulating autophagy in irradiated cells. Supported by 2U19A1068021-06 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 2495. doi:10.1158/1538-7445.AM2011-2495