Dimethyl Fumarate Controls the NRF2/DJ-1 Axis in Cancer Cells: Therapeutic Applications.

The transcription factor NRF2 (NFE2L2), regulates important antioxidant and cytoprotective genes. It enhances cancer cell proliferation and promotes chemoresistance in several cancers. Dimethyl fumarate (DMF) is known to promote NRF2 activity in noncancer models. We combined in vitro and in vivo methods to examine the effect of DMF on cancer cell death and the activation of the NRF2 antioxidant pathway. We demonstrated that at lower concentrations (<25 µmol/L), DMF has a cytoprotective role through activation of the NRF2 antioxidant pathway. At higher concentrations, however (>25 µmol/L), DMF caused oxidative stress and subsequently cytotoxicity in several cancer cell lines. High DMF concentration decreases nuclear translocation of NRF2 and production of its downstream targets. The pro-oxidative and cytotoxic effects of high concentration of DMF were abrogated by overexpression of NRF2 in OVCAR3 cells, suggesting that DMF cytotoxicity is dependent of NRF2 depletion. High concentrations of DMF decreased the expression of DJ-1, a NRF2 protein stabilizer. Using DJ-1 siRNA and expression vector, we observed that the expression level of DJ-1 controls NRF2 activation, antioxidant defenses, and cell death in OVCAR3 cells. Finally, antitumoral effect of daily DMF (20 mg/kg) was also observed in vivo in two mice models of colon cancer. Taken together, these findings implicate the effect of DJ-1 on NRF2 in cancer development and identify DMF as a dose-dependent modulator of both NRF2 and DJ-1, which may be useful in exploiting the therapeutic potential of these endogenous antioxidants. Mol Cancer Ther; 16(3); 529-39. ©2017 AACR.

Oxidative stress markers are increased since early stages of infection in syphilitic patients.

Clinical symptoms of syphilis are the consequence of the spirochete propensity to induce persistent chronic inflammation, which could participate to oxidative stress increase. The present study was designed to evaluate the level of oxidative stress biomarkers and antioxidant defences in a cohort of syphilitic patients. Serum oxidative status was explored in 63 patients diagnosed with early syphilis, 34 consulting patients negative for syphilis and 19 healthy controls. Total plasma thioredoxin (Trx) and thiols were determined as antioxidant capacity markers, °NO, advanced oxidation protein products (AOPP) and protein carbonyl levels as oxidative stress status biomarkers, and CRP as marker of inflammation. Mean serum levels of Trx, AOPP, carbonyls, and nitrates/nitrites were significantly higher, whereas thiols level was lower in syphilitic patients compared to non-syphilitic patients and healthy controls (respectively, p < 0.05/p < 0.01 for Trx, p < 0.005/p < 0.0001 for AOPP, p < 0.05/p < 0.005 for carbonyls, p < 0.005/p < 0.05 for nitrates/nitrites and p < 0.01/p < 0.0001 for thiols). According to the stage of the disease, results highlighted a marked and sustained oxidative stress imbalance from the first stage to the latent period of the disease. Moreover, syphilitic patients presented a low inflammation status reflected by median of CRP level (1.7 mg/L, range 5th-95th percentile from <0.1 to 33.7 mg/L), correlated with antioxidant capacity decrease (thiols) at stage 1 (r = -0.725; p < 0.0001) and nitrosative stress increase (nitrates/nitrites) at stage 2 and latent (respectively, r = 0.285, p < 0.05 and r = 0.650, p < 0.05). These findings indicate that at all stages of the disease, despite a low-grade inflammatory state, syphilis infection generates a major oxidative and nitrosative stress which may be involved in the pathophysiology of the disease.