Bioactivity of quinoxaline-1,4-dioxide derivatives in radioresistant tumour cells exposed to radiotherapy

Abstract

Quinoxaline-1,4-dioxide derivatives are synthetic heterocyclic compounds with multiple biological and pharmacological effects, including anticancer activity. Carcinogenesis is a complex process characterized by a multitude of cell mechanisms. However, the resistance and multidrug resistance of certain tumours to therapy remains a high priority research. Previous studies of our group with quinoxaline-1,4-dioxide (QNX) derivatives demonstrated a biotoxicity action in bacterial models and their capability to promote cell damage by the production of reactive oxygen species (ROS). In this study, we investigated the bioactivity of quinoxaline-1,4-dioxide (QNX), 2-methylquinoxaline-1,4-dioxide (2MQNX), 3-methyl-2-quinoxalinecarboxamide-1,4-dioxide (3M2QNXC), 2-amino-3-cyanoquinoxaline-1,4-dioxide (2A3CQNX) and 2-hidroxiphenazine-1,4-dioxide (2HF) in different animal cell lines to determine their cytotoxicity and potential radiation chemosensitizing action in radioresistante cell models submitted to Radiotherapy. In vitro cell cultures were used to evaluate the influence of quinoxaline-1,4-dioxide derivatives in viability, migration and proliferation of non-malignant (3T3-L1 and HMVEC-D) and malignant (B16-F10, MeWo, GL-261 and BC3H1) cell lines and their influence in metabolic activity, catalase activity, glutathione and 3-nitrotyrosine (3-NT) quantitation by HPLC in malignant melanocytes (B16-F10, MeWo) and brain tumour cells (GL-261 and BC3H1) submitted to radiotherapy treatments (total dose of 6 Gy) was evaluated. The viability IC50 concentrations for each quinoxaline-1,4-dioxide derivatives were calculated, and a concomitant reduction of migration and proliferation was observed mainly in malignant cell lines. QNX and 2MQNX decrease the tumour cell viability with higher IC50 when compared to 3M2QNCX, 2A3CQNX and 2HF. 2HF demonstrated the most pronounced cytotoxic effects in all cell lines tested with the lowest IC50 values. 2HF exhibited potent anti-viability, anti-migration and antiproliferative actions selectively in tumour cells. 2A3CQNX, 2HF, and 3M2QNXC decrease antioxidant cell defences, decreasing the quantification of GSH in the non-irradiated tumour cell lines. After irradiation, quinoxaline-1,4-dixides derivatives sensitize radiation action, decreasing catalase activity, GSH values and increasing 3-NT levels. In overall, quinoxaline-1,4-dioxides derivatives presented a cytotoxic effect on tested cell lines, with the decrease of cell viability, cell migration and cell proliferation. Quinoxaline-1,4-dioxides derivatives modulate the oxidative status in malignant melanocytes and brain tumour cell lines and exhibited a potential radiosensitizer in vitro action, decreasing antioxidant cell defences, specifically glutathione synthesis, modifying the intrinsic radioresistance of cell lines in study. Once more, 2HF produced unrecoverable cell damages in irradiated and non-irradiated human malignant melanocytes (MeWo) and glioma cell lines. Nevertheless, further molecular and in vivo studies are requesting to clarification of the cellular mechanism of action of these quinoxaline derivatives.