Upregulation of cellular protective mechanisms against oxidative damage via pharmacological intervention

Abstract

Oxidative damage is widely accepted as a major stress factor responsible for many age‐related diseases, as well as other degenerative conditions associated with normal aging. We initially became interested in activating or upregulating cellular protective mechanisms against oxidative damage after identifying methionine sulfoxide reductase A (MSRA), the first member of the MSR family of enzymes. The MSR system, MSRA and MSRB, reduces methionine sulfoxide residues in proteins, both the S and R epimers, back to methionine, repairing oxidative damage to proteins. MSRA can also reduce small molecules that contain a methyl sulfoxide S epimer, including the prodrug sulindac, that is converted to sulindac sulfide, the active NSAID (nonsteroidal anti‐inflammatory drug). We reported that sulindac can also protect both retinal pigmented epithelial (RPE) cells against chemical oxidative damage, and the heart against ischemia/reperfusion damage (I/R), by initiating a protective response, similar to ischemic preconditioning. This mechanism of sulindac protection was shown to be independent of its NSAID activity. In contrast, sulindac under similar conditions, sensitizes cancer cells to oxidative stress, resulting in enhanced killing of the cancer cells when they are exposed to additional stress. Because of sulindac's unique properties the National Institute of Aging recently selected sulindac to test for life span extension in mice in their Interventions Testing Program. In order to find a more active sulindac derivative that could protect cells against oxidative damage and lacked NSAID activity, we screened a series of sulindac derivatives containing a central indenyl core present in the sulindac scaffold. We have identified a compound, MCI‐100, that is not an NSAID, that is >20 fold more active than sulindac in protecting RPE cells from oxidative damage and also more active than sulindac in protecting the heart against I/R damage in a Langendorff ex‐vivo model. Additional experiments suggest that the protective mechanism of both sulndac and MCI‐100 may be related to their ability to inhibit PDE10, resulting in an increase in intracellular cGMP levels, that could initiate a pharmacological preconditioning response through PKG activation. However, unlike sulindac, MCI‐100 does not sensitize cancer cells to oxidative stress.Our eventual goal is to develop drug combinations that up‐regulate several different mechanisms that cells use to protect against oxidative damage, as a therapeutic approach to slow the progression of age related diseases, and treat other diseases that involve oxidative damage.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.