title: 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 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.
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Huang
authors.forename: Caihua
authors.initials: C
authors.lastname: Zhu
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
authors.forename: George
authors.initials: G
authors.lastname: Qiao
authors.forename: Despina
authors.initials: D
authors.lastname: Komninou
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010084:Oxidation-Reduction; D011073:Polyamines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology*; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D000970:Antineoplastic Agents; D018844:Cyclin-Dependent Kinases; D051545:Cyclooxygenase 1; D015232:Dinoprostone; D000518:Eflornithine; D011073:Polyamines; D017382:Reactive Oxygen Species; D013467:Sulindac; D000099228:Diamine N-Acetyltransferase