Abstract 4159: Circadian clock protects against radiation-induced dermatitis and cardiomyopathy in mice

Abstract

Abstract Radiation therapy (RT) is commonly used in cancer treatment. Despite technological advances to improve precision external-beam RT in treating breast, lung, and esophageal tumors, a substantial number of patients receive radiation to their hearts and the external skin region. This radiation insult results in acute and chronic toxicities including dermatitis and cardiomyopathy, affecting the patient's quality of life and survival. Hence, reducing toxicities associated with RT are desirable outcomes. With the knowledge that the natural circadian clock, present in almost every cells of the body including the skin and heart, regulates DNA repair, cell death and proliferation, and cardiac function processes, we hypothesize that molecular defensive mechanisms of the circadian system play regulatory roles to minimizing RT-induced skin and heart toxicity in cancer patients. To investigate acute toxicity of RT, studies were performed using SKH-1 hairless mice with healthy clock (wild-type day shift (DS)) and environmentally disrupted clock (wild-type rotating shift (RS) and genetically disrupted clock (Per1/2 knockout (Per1/2-/-)) conditions. We treated all groups (n=9 mice per group) with a single dose RT (6 grays of ionizing radiation) to the whole body. We used body weight as an indicator of overall toxicity, red spots as a measure of dermatitis, and left ventricular ejection fraction (LVEF) by ultrasound echocardiography as a readout for cardiomyopathy, relative to the measurements pre-RT as controls. After sacrifice, genotoxicity was detected using alkaline comet assay in PBMCs. Worse toxicities were observed until 2 weeks post-RT in mice with circadian clock disruption compared to mice with healthy clocks. Body weights of the disrupted clock groups were significantly reduced by up to 10% on day 2, unlike the DS group which reduced by only 2%. However, there was body weight loss recovery from day 6 in clock disrupted mice but this recovery was not sustained in Per1/2-/- mice. Dermatitis was counted where visible and there was 2.4- and 1.7- fold increases in RS and Per1/2-/- mice compared to DS mice. In the heart, LVEF was significantly decreased in RS and Per1/2-/- mice by days 1 and 4, and began to recover by day 8 in RS. Comparatively, the LVEF in DS mice was not significantly reduced. On a cellular level, genotoxicity in blood cells were significantly increased in RS and Per1/2-/- mice relative to DS mice. Taken together, these findings strongly suggest that the healthy circadian clock protects the whole body, skin, and heart from RT-induced toxicity. Future work includes mechanistic understanding of how the natural circadian clock system can be harnessed to minimize toxicity against RT. The successful completion of this project will provide a novel mechanistic understanding into the protective role of the circadian clock against acute and chronic skin and heart toxicities for cancer patients undergoing RT. Citation Format: Panshak P. Dakup, Kenneth I. Porter, Zhaokang Cheng, Shobhan Gaddameedhi. Circadian clock protects against radiation-induced dermatitis and cardiomyopathy in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4159.