BMX-001, a selective radioprotector in phase II clinical trials, can reverse radiation-induced fibrosis when given three weeks after radiation [RNA-seq]

To assess whether BMX-001’s protection is contingent on Nrf2 expression, we evaluated the effect of BMX-001 on 5-FU treated bone marrow, where Nrf2 is crucial to maintaining hematopoietic stem cell niches. Interestingly, BMX-001 could still exert some chemoprotection in mice without functional Nrf2. To assess whether BMX-001 had any functional effects on protein oxidation status, we performed mass spectrometry on sulfenylated proteins in bone marrow treated with 5-FU in wildtype mice and mice without Nrf2.

We found that BMX-001 given before 5-FU treatment resulted in the sulfenylation of CRTC2 and CBP, two proteins involved in CREB signaling and known to enhance Nrf2 activity. We also found that BMX-001 with 5-FU treatment enhanced DPYD sulfenylation, a protein known to detoxify 5-FU, and ALDH7A1 sulfenylation, a protein known to detoxify aldehydes. Together, these results suggest that BMX-001 can protect against oxidative stress in normal tissue via Nrf2 dependent and independent mechanisms.