Anticancer Effect of Deuterium Depleted Water-Redox Disbalance Leads to Oxidative Stress

The antiproliferation effect of deuterium depleted water (DDW) is well documented, but the mechanism remained elusive. Here three complementary proteomics approaches applied to A549 cells revealed a disbalance brought about by DDW in mitochondria between ROS production and neutralization, thus leading to oxidative stress in the cells. Subsequent validation by orthogonal approaches supported this scenario. Therefore, DDW has potential as an adjuvant in antitumor therapy, especially in the modalities inducing oxidative stress in cancer cells. Despite the convincing empirical evidence that deuterium depleted water (DDW, 25?125 ppm deuterium) has anticancer effect, the molecular mechanism remains unclear. Here, redox proteomics investigation of the DDW action in A549 cells revealed an increased level of oxidative stress, whereas expression proteomics in combination with thermal profiling uncovered crucial role of mitochondrial proteins. In the proposed scenario, reversal of the normally positive deuterium gradient across the inner membrane leads to an increased export of protons from the matrix to intermembrane space and an increase in the mitochondrial membrane potential, enhancing the production of reactive oxygen species (ROS). The resulting oxidative stress leads to slower growth and can induce apoptosis. However, further deuterium depletion in ambient water triggers a feedback mechanism, which leads to restoration of the redox equilibrium and resumed growth. The DDW-induced oxidative stress, verified by traditional biochemical assays, may be helpful as an adjuvant to ROS-inducing anticancer therapy.