Metabolic Modulation by Dimethyl Fumarate Alters Docetaxel Responses in Prostate Cancer Cells

Dimethyl fumarate (DMF) is a clinically approved fumarate ester with pleiotropic effects and a promising candidate for drug repurposing in cancer. Here, we investigated whether low-dose DMF could modulate docetaxel (DCT) responses in prostate cancer cells. PC-3, LNCaP, and RWPE-1 cells were exposed to DMF and DCT individually or in combination, and cell viability, drug interaction profiles, apoptosis, oxidative stress, mitochondrial mass, glutathione status, glucose consumption, lactate production, LDHA/SOD2 expression, and oxygen consumption were evaluated. Low-dose DMF and DCT were well-tolerated in RWPE-1 normal prostate cells. In prostate cancer cells, the DMF-DCT combination was cytotoxic and strongly dose- and ratio-dependent, with the most favorable responses at higher exposures and under balanced or DCT-enriched regimens. DMF-DCT-treated LNCaP cells showed reduced viability, decreased lactate production, increased glucose consumption, mitochondrial dysfunction, oxidative stress, downregulation of LDHA and SOD2, and caspase-associated apoptosis. In contrast, PC-3 cells showed greater combinatorial susceptibility, a docetaxel dose-sparing effect, and a low glycolytic profile, with concomitant cytotoxicity and mitochondrial dysfunction. These findings identify DMF as a context-dependent metabolic modulator of docetaxel response, supporting further evaluation of DMF-DCT combinations as a potential therapeutic strategy in prostate cancer.