Phospho-sulindac (OXT-922) inhibits the growth of human colon cancer cell lines: a redox/polyamine-dependent effect.
Abstract
Non-steroidal anti-inflammatory drugs such as sulindac are promising chemoprevention agents against colon cancer, but their weak potency and side effects limit their use for both chemoprevention and chemotherapy. Here, we evaluated the effect of a new sulindac derivative, phospho-sulindac or OXT-922, on the growth of human cancer cell lines and its mechanism of action. OXT-922 inhibited the growth of human cancer cell lines originating from colon, pancreas and breast ~11- to 30-fold more potently than sulindac. This effect was mediated by a strong cytokinetic effect. Compared with control, OXT-922 inhibited cell proliferation by up to 67%, induced apoptosis 4.1-fold over control and blocked the G(1) to S cell cycle phase transition. OXT-922 suppressed the levels of cell cycle regulating proteins, including cyclins D(1) and D(3) and Cyclin-dependent kinases (CDK) 4 and 6. The levels of intracellular reactive oxygen species (ROS), especially those of mitochondrial O₂ⁱ⁻, were markedly elevated (5.5-fold) in response to OXT-922. ROS collapsed the mitochondrial membrane potential and triggered apoptosis, which was largely abrogated by antioxidants. OXT-922 suppressed nuclear factor-kappaB activation and downregulated thioredoxin-1 e...Continue Reading
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