Current chemotherapy approaches for cancer treatment lack selective cytotoxicity, causing unwanted side effects. Recent literature studies have shown that cancer cells show elevated levels of reactive oxygen species (ROS). For example, melanomas are characterized by an increased rate of ROS production, which is the result of metabolic changes and altered redox balance that accompanies the malignant transformation. The difference in redox state between normal and melanoma cells opens an important therapeutic window that can be exploited. Because melanoma cells have an intrinsic capacity to acquire resistance to drugs, treatment of invasive tumors is very difficult, resulting in very poor prognosis of this metastatic disease. In this study, we evaluated the effect of RAC1, a novel agent that is activated by ROS and acquires the ability to bind to DNA, causing cell death. Using a panel of human melanoma cell lines carrying different genetic mutations, we found that 5 out of 7 display higher sensitivity to the drug when compared to normal human melanocytes (NMC). Through kinetic studies to determine agent half-life, single cell gel electrophoresis to detect DNA damage, Western blotting to measure protein expression levels, and <i>in vivo</i> tumor studies, we revealed that the high levels of ROS displayed by melanoma cells can be exploited for the further development of a more selective DNA damaging agent.<br/>

Development of a selective and stable anti-cancer agent by exploiting high levels of reactive oxygen species

253rd National Meeting (2017)

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