miRNA675-5p inhibitor’s dual role as novel therapeutic alternative or sensitizing treatment in resistant glioma models

Glioma is currently the most aggressive CNS tumor. MicroRNA (miRNA)675-5p is a hypoxic miRNA involved in promoting and maintaining the hypoxia inducible factor (HIF)-1α pathway, the driving force for glioma proliferation, migration into surrounding tissue, and resistance. Its inhibition is effective in reducing HIF-1α and all pathways related to it. However, the molecular mechanism through which miRNA inhibition is effective has not yet been fully elucidated. The therapeutic efficacy of the miRNA675-5p inhibitor was tested in a panel of resistant glioma lines evaluating the cellular, molecular, and biochemical rearrangement of the cells after treatment, with particular attention to the oxidative stress imbalance. miRNA675-5p inhibitor has a therapeutic efficacy on its own in resistant cell lines, reducing HIF-1α and its related pathways. The mechanism through which this occurs is the induction of oxidative stress. Its impairment, in fact, reverses the cytotoxic effect. Inhibitor-treated cells acquire metabolic characteristics clearly distinct from untreated cells, triggering compensatory mechanisms that must be considered for the secondary treatment of glioma with temozolomide. The induction of oxidative stress and metabolic rearrangement play key roles in the cytotoxic effect of the miRNA675-5p inhibitor, which could be proposed as a new therapeutic approach in glioma.