RADIATION-INDUCED TISSUE DAMAGE IS ATTENUATED BY AN NRF2 INDUCER

B.J. Bormann

Supportive Therapeutics, LLC, Cambridge, MA, USA

Abstract

Nuclear factor erythroid 2-related factor (Nrf2) is a transcriptional factor that regulates many antioxidants and when up-regulated effectively mitigates oxidative stress and inhibits drivers of the inflammatory events that contribute to tissue damage resulting from radiation. We have been testing an Nrf2 inducer (oltipraz/ST-617) with the hypothesis that such an agent can reduce free radical formation resulting in a diminution of radiation tissue damage such as oral mucositis. Quantitative PCR on primary gingival cells treated with ST-617 was used to measure the up-regulation by Nrf2 of glutamate cysteine lyase (GLGC). GCLC was significantly enhanced in ST-617 treated gingival cells, supporting that the mechanism of action of ST-617 is via Nrf2 activation. We tested the ability of Nrf2 activation by ST-617 to attenuate tissue damage in an acute radiation model in hamsters. Using this model, the cheek pouch of the hamster is everted and exposed to 40 Gy of radiation. This radiation dose produces clinically-meaningful ulceration of the cheek pouch mucosa. Studies conducted with ST-617 consistently produced a significant decrease in the total number of days with ulceration of the mucosa. This hamster model has also proven to be predictive of human response. Future studies will determine the effect of ST-617 treatment on the attenuation of oral mucositis during the chemoradiation treatment of head and neck cancer patients.

Keywords: Nrf2, oltipraz, mucositis, radiation.