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 expression. It also suppressed the production of
prostaglandin E(2) and decreased
cyclooxygenase-1 expression. Similar to
sulindac, OXT-922 enhanced
spermidine/spermine N(1)-acetyltransferase activity, reduced the cellular
polyamine content and synergized with
difluoromethylornithine to inhibit
cancer cell proliferation and induce apoptosis. Our results suggest that OXT-922 possesses promising anticancer properties and deserves further evaluation.