Metabolic reprogramming in diffuse intrinsic pontine gliomas (DIPG): dual inhibition of mitochondrial oxidative phosphorylation and lactate metabolism to enhance anti-tumor and radiosensitizing effects in DIPG cells

Metabolic acidosis disrupts the proton gradient across mitochondrial membranes, which decreases the efficiency of ATP production.

In brain cancer cells derived from patients, dichloroacetate changes how the cells use glucose, causing them to produce less acid and less lactate by increasing energy production in mitochondria.

Phenformin and dichloroacetate together lower oxygen deprivation and HIF-1α protein levels in laboratory-grown DIPG brain tumor cells.

In laboratory-grown brain tumor cells derived from patients, a combination of two drugs—phenformin and dichloroacetate—lowers lactate levels, reduces energy production through mitochondria and glycolysis, and triggers cell death through ATP loss, oxidative stress, DNA damage, and apoptosis.

In mice with DIPG brain tumors, a combination of phenformin, dichloroacetate, and radiotherapy causes weight loss and does not increase survival time compared to radiotherapy alone over four weeks.

The drugs phenformin and dichloroacetate together increase markers of DNA damage and reduce a key repair protein in DIPG brain cancer cells, leading to impaired DNA repair.