Pifithrin-alpha (PFT-alpha) caused differential protection of rat liver cells and HepG2 cell line in response to the selective cytotoxicity of arsenic and cadmium.

In response to genotoxic agents, normal cells are instructed by p53 to either perform DNA repair or to commit suicide. Since chemo and/or radiotherapy damage both normal and cancerous cells, the use of PFT-alpha, a reversible inhibitor of down stream function of p53, was suggested as a temporary inhibitor of p53-induced cell damage. Our objective therefore, was (1) to assess the inherent response of HepG2 and rat liver cells to the effects of arsenic and cadmium and (2) to evaluate the role of PFT-alpha in the differential protection of rat liver and HepG2 cells. Following cellular growth to 90% confluency, exposure to cytotoxic agents in presence of PFT-alpha (10 ppm) or its absence was performed. Cell survival was detected fluorometrically using fluorescein diacetate (FDA) and an Ascent Fluoroskan. Toxicity index (LC50) was calculated from percent survival using regression analysis. Results showed an average of 46 fold inherent resistance of rat liver cells to arsenic in comparison to HepG2 cells (LC50 range of 573.15-670 vs. 13.4-13.7 ppm respectively). An average of 8 fold inherent resistance was also attributed to rat liver cells in response to cadmium (LC50 range of 57.72-58.1 vs. 6.99-7.35 ppm respectively). PFT-alpha did not show significant difference in protecting HepG2 cells against cadmium or arsenic. In contrast, there was significant difference in the protection of rat liver cells upon exposure to arsenic. We conclude that Pifithrin-alpha exhibits protection to normal cells, which can play an important role in cancer chemotherapy.