Despite the available therapeutic options, hepatocellular carcinoma is still responsible for many cancer-related deaths. Novel synthetic compounds have been developed as promising drugs in cancer therapy, including organoselenium, organosulfur and indolic compounds. The present work evaluated the cytotoxic effects of new 15 selenylindoles and thiophenylindoles on HepG2 cells. The screening of the chalcogenylindoles by the MTT method evidenced that the trifluoromethyl-substituted derivatives were the most cytotoxic and promoted a significant reduction in HepG2 cells viability starting at 20 μM after 24 h and at 10 μM and 15 μM after 48 h for the selenylindol and thiophenylindol, respectively. The increased release of lactate dehydrogenase, the alterations in cell morphology, such as the presence of membrane blebbing, and the annexin V and propidium iodide staining also confirmed their cytotoxicity. Furthermore, both compounds significantly enhanced reactive oxygen species (ROS) levels in HepG2 cells after 48 h and impaired cell cycle progression at the G2/M phases after 24 h, simultaneously increasing DNA fragmentation levels. The chalcogenylindoles also affected hepatocarcinoma cells' metabolism, as evidenced by the stimulus of the basal state of respiration, the increased levels of lactate in the culture medium, as well by the depletion in ATP levels. Overall, the results support the cytotoxicity of the trifluoromethylated selenylindol and thiophenylindol, by cell death associated with augmented ROS levels, impaired cell cycle progression and altered metabolism.
