13-hydroxy-9-11-octadecadienoic-acid and sulindac-sulfone

We previously found (I. Shureiqi et al., Carcinogenesis (Lond.), 20: 1985-1995, 1999; I. Shureiqi et al, J. Natl. Cancer Inst., 92: 1136-1142, 2000) that (a) 15-lipoxygenase-1 (15-LOX-1) protein and its product 13-S-hydroxyoctadecadienoic acid (13-S-HODE) are decreased; and (b) nonsteroidal anti-inflammatory drug (NSAID)-induced 15-LOX-1 expression is critical to NSAID-induced apoptosis in colorectal cancer cells expressing cyclooxygenase-2 (COX-2). We used the NSAIDs sulindac sulfone (COX-2-independent) and NS-398 (a COX-2 inhibitor) to assess NSAID upregulation of 15-LOX-1 in relation to COX-2 inhibition during NSAID-induced apoptosis in the DLD-1 (COX-2-negative) colon cancer cell line. We found that: (a) NSAIDs up-regulated 15-LOX-1, which preceded apoptosis; and (b) 15-LOX-1 inhibition blocked NSAID-induced apoptosis, which was restored by 13-S-HODE but not by its parent, linoleic acid. NSAIDs can induce apoptosis in colon cancer cells via up-regulation of 15-LOX-1 in the absence of COX-2.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; Antithrombins; Apoptosis; Arachidonate 15-Lipoxygenase; Arachidonic Acid; Blotting, Western; Caffeic Acids; Cell Line; Colonic Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Hydroxyeicosatetraenoic Acids; Isoenzymes; Linoleic Acid; Linoleic Acids; Membrane Proteins; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Recombinant Proteins; Sulfonamides; Sulindac; Time Factors; Tumor Cells, Cultured; Up-Regulation