GSH and Cancer Initiation

There has been a long-standing belief that supplementation with antioxidants could prevent or treat cancer. However, results of large-scale clinical trials have proven the opposite: supplementation with antioxidants promote, rather than prevent, cancer. While these findings were indisputable, the mechanism behind these surprising results was lacking. A mechanism explaining the failure of antioxidants in preventing cancer was provided when it was demonstrated that the antioxidant GSH was required for cancer initiation (Harris, I.S., Cancer Cell, 2015). Since the systemic deletion of the catalytic enzyme in GSH synthesis (Gclc) in mice is embryonically lethal, a viable knockout of the GCLC modifying subunit (Gclm) was utilized with a ~75% reduction in GSH levels and without any gross phenotype. Crossing these mice to multiple spontaneous tumor models revealed that reduced GSH synthesis prevented the development of malignant cells. This result and subsequent mechanistic studies confirmed that cancer cells utilize antioxidants during tumor initiation to mitigate ROS levels.

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