Work

Sodium Butyrate Inhibits Glyoxalase 1 to Reverse D-Lactate-associated Drug Resistance in Cancer Cells

Year: 2026

Type: article

Abstract: Drug resistance remains a major limitation to effective cancer therapy, and its metabolic basis is incompletely understood. We recently developed models of acquired drug resistance through chronic exposure of tumor cells to anticancer agents and identified a metabolic phenotype characterized by impaired mitochondrial bioenergetics, increased L-lactate production, and decreased oxygen consumption rate (OCR). Here, we investigated the contribution of D-lactate metabolism to this phenotype. Compared with their parental (P) counterparts, drug-resistant (R) cell lines showed increased D-lactate production together with increased glyoxalase 1 (GLO1) expression and activity. Sodium butyrate (NaB) reduced GLO1 expression and activity in tumor cell lines with higher expression of D-lactate pathway components, and NaB treatment was associated with reduced intracellular D-lactate levels and increased sensitivity to the corresponding anticancer treatments in selected cell models. These findings support a biochemical link between NaB-mediated modulation of the GLO1/D-lactate pathway and drug response, without excluding additional NaB-dependent mechanisms. Furthermore, NaB enhanced the effects of pro-differentiation agents in the tested in vitro models. Together, our data identify the GLO1/D-lactate pathway as a metabolic feature associated with drug resistance and support further investigation of NaB-based strategies in appropriate preclinical models.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113694