Metformin hydrochloride, an antihyperglycemic agent, and sulindac, a nonsteroidal anti-inflammatory drug, are FDA-approved drugs known to exert anticancer effects. Previous studies demonstrated sulindac and metformin's anticancer properties through mitochondrial dysfunction and inhibition of mitochondrial electron transport chain complex I and key signaling pathways. In this study, various drugs were administered to A549 lung cancer cells, and results revealed that a combination of sulindac and metformin enhanced cell death compared to the administration of the drugs separately. To measure superoxide production over time, we employed a time-lapse fluorescence imaging technique using mitochondrial-targeted hydroethidine. Fluorescence microscopy data showed the most significant increases in superoxide production in the combination treatment of metformin and sulindac. Results showed significant differences between the combined drug treatment and control groups and between the positive control and control groups. This approach can be utilized to quantify the anticancer efficacy of drugs, creating possibilities for additional therapeutic options.

Oxidative damage is believed to play a major role in the etiology of many age-related diseases and the normal aging process. We previously reported that sulindac, a cyclooxygenase (COX) inhibitor and US Food and Drug Administration–approved anti-inflammatory drug, has chemoprotective activity in cells and intact organs by initiating a pharmacological preconditioning response, similar to ischemic preconditioning. The mechanism is independent of its COX inhibitory activity, as suggested by studies on the protection of the heart against oxidative damage from ischemia-reperfusion and retinal pigmented endothelial (RPE) cells against chemical oxidative and UV damage. Unfortunately, sulindac is not recommended for long-term use due to toxicities resulting from its COX inhibitory activity. To develop a safer and more effective derivative of sulindac, we screened a library of indenes and identified a lead compound, MCI-100, that lacked significant COX inhibitory activity but displayed greater potency than sulindac to protect RPE cells against oxidative damage. MCI-100 also protected the intact rat heart against ischemia-reperfusion damage following oral administration. The chemoprotective activity of MCI-100 involves a preconditioning response similar to sulindac, which is supported by RNA sequencing data showing common genes that are induced or repressed by sulindac or MCI-100 treatment. Both sulindac and MCI-100 protection against oxidative damage may involve modulation of Wnt/β-catenin signaling, resulting in proliferation while inhibiting transforming growth factor-β signaling, leading to apoptosis. In summary MCI-100, is more active than sulindac in protecting cells against oxidative damage, but without significant nonsteroidal anti-inflammatory drug activity, and could have therapeutic potential in treatment of diseases that involve oxidative damage. SIGNIFICANCE STATEMENT In this study, we describe a novel sulindac derivative, MCI-100, that lacks significant COX inhibitory activity, but is appreciably more potent than sulindac in protecting retinal pigmented epithelial cells against oxidative damage. Oral administration of MCI-100 markedly protected the rat heart against ischemia/reperfusion damage. MCI-100 has potential therapeutic value as a drug candidate for age-related diseases by protecting cells against oxidative damage and preventing organ failure.

Our results show that the plasmid DNA induced the expression of APP in transfected SHSY5Y cells compared to untransfected cells and the expression of APP was strongest at 24 h. We observed that the cell proliferation decreased in APP transfected cells in both hypoxic and normoxic conditions. Further, reduced cell proliferation was seen under hypoxic conditions compared to normoxic conditions indicating that hypoxic conditions further exacerbateAD pathology. Our findings in an in vitro AD model, suggest that sulindac has a potential therapeutic value to ameliorate AD pathology.