Gliomas are a malignant tumor group whose patients have survival rates around 12 months. Among the treatments are the alkylating agents as temozolomide (TMZ), although gliomas have shown multiple resistance mechanisms for chemotherapy. Guanosine (GUO) is an endogenous nucleoside involved in extracellular signaling that presents neuroprotective effects and also shows the effect of inducing differentiation in cancer cells. The chemotherapy allied to adjuvant drugs are being suggested as a novel approach in gliomas treatment. In this way, this study evaluated whether GUO presented cytotoxic effects on human glioma cells as well as GUO effects in association with a classical chemotherapeutic compound, TMZ. Classical parameters of tumor aggressiveness, as alterations on cell viability, type of cell death, migration, and parameters of glutamatergic transmission, were evaluated. GUO (500 and 1000 μM) decreases the A172 glioma cell viability after 24, 48, or 72 h of treatment. TMZ alone or GUO plus TMZ also reduced glioma cell viability similarly. GUO combined with TMZ showed a potentiation effect of increasing apoptosis in A172 glioma cells, and a similar pattern was observed in reducing mitochondrial membrane potential. GUO per se did not elevate the acidic vesicular organelles occurrence, but TMZ or GUO plus TMZ increased this autophagy hallmark. GUO did not alter glutamate transport per se, but it prevented TMZ-induced glutamate release. GUO or TMZ did not alter glutamine synthetase activity. Pharmacological blockade of glutamate receptors did not change GUO effect on glioma viability. GUO cytotoxicity was partially prevented by adenosine receptor (A1R and A2AR) ligands. These results point to a cytotoxic effect of GUO on A172 glioma cells and suggest an anticancer effect of GUO as a putative adjuvant treatment, whose mechanism needs to be unraveled.
Keywords: A172 glioma cells; Adenosine; Cytotoxicity; Glutamate; Guanosine; Temozolomide.