AbstractNonsteroidal anti-inflammatory drugs such as sulindac are promising chemoprevention agents against colon cancer. However, their weak potency and side effects limit their use for both chemoprevention and chemotherapy. Here we explored the effect of a novel sulindac derivative, MDC-922, on human cancer cells lines and explored its mechanism of action. MDC-922 inhibited the growth of human cancer cell lines originating from colon, pancreas and breast about 11- to 30-fold more potently than sulindac. It inhibited cell proliferation by up to 67% and significantly induced a G1/S phase cell cycle arrest. MDC-922 suppressed the levels of cell cycle regulating proteins including cyclin D1/D3 and CDK 4/6. The levels of intracellular reactive oxygen species (ROS), especially those of the mitochondrial superoxide anion were markedly elevated in response to MDC-922; ROS collapsed the mitochondrial membrane potential and triggered apoptosis, which was largely abrogated by the antioxidant N-acetyl cysteine. Interestingly, the expression of thioredoxin-1, a small redox protein which is essential for cell proliferation and survival, was rapidly downregulated (but not oxidized) by MDC-922, suggesting a unique ROS-inducing mechanism of MDC-922. Signaling pathways including cyclooxygenase (COX), nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were modulated by MDC-922. Like sulindac, MDC-922 enhanced spermidine/spermine N1-acetyltransferase (SSAT) activity, reduced the cellular polyamine content and synergized with DFMO to inhibit cancer cell proliferation and induce apoptosis. Our results suggest that MDC-922 possesses promising anti-cancer properties and deserves further evaluation.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4468.