Abstract
<title>Abstract</title> <p>Resistance to temozolomide (TMZ) limits the efficacy of treatment in glioblastoma (GBM) and it is fuelled by a metabolic reprogramming of the cancer cells. Lonidamine (LND), a glycolytic and mitochondrial inhibitor, was used in combination with TMZ to evaluate metabolic and microstructural changes in a GBM model. C57BL/6 mice bearing intracranial GL261 tumours were treated with saline, LND, TMZ, or LND + TMZ for five consecutive days. In vivo longitudinal MRI included diffusion weighted imaging (DWI), and lactate-edited ¹H-MRS and the results were confirmed with immunohistochemistry for MCT4 expression. In vitro, acute and chronic bioenergetic reprogramming of GL261 cells was assessed. A significant decrease in lactate was observed in the LND and LND + TMZ groups indicating a change in their glycolytic flux. This metabolic shift was consistent with a marked reduction in MCT4 protein, the lactate transporter. In vitro bioenergetic profiling revealed an acute decrease in mitochondrial respiration, with partial recovery at later time points. Although a limited therapeutic benefit of addition LND to TMZ was observed, its tumour-selective activity and effect on tumour microenvironment seems promising and its long-term effects on tumour development should be investigated as part of an optimized combination strategy for TMZ treatment.</p>