tNOX, an alternative target to COX-2 to explain the anticancer activities of non-steroidal anti-inflammatory drugs (NSAIDS).
Our work has identified a cancer-specific, cell surface and growth-related quinol oxidase with both NADH oxidase and protein disulfide-thiol interchange activities, a member of the ECTO-NOX protein family designated tNOX. We provide evidence for tNOX as an alternative drug target to COX-2 to explain the anticancer activity of COX inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDS), piroxicam, aspirin, ibuprofen, naproxen and celecoxib all specifically inhibited tNOX activity of HeLa (human cervical carcinoma) and BT-20 (human mammary carcinoma) cells (IC(50) in the nanomolar range) without effect on ECTO-NOX activities of non-cancer MCF-10A mammary epithelial cells. With cancer cells, rofecoxib was less effective and two NSAIDS selective for COX-1 were without effect in inhibiting NOX activity. The IC(50) for inhibition of tNOX activity of HeLa cells and the IC(50) for inhibition of growth of HeLa cells in culture were closely correlated. The findings provide evidence for a new drug target to account for anticancer effects of NSAIDS that occur independent of COX-2.
Morré
D James
DJ
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA. morre@pharmacy.purdue.edu
Morre
Dorothy M
DM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D009363:Neoplasm Proteins; D051546:Cyclooxygenase 2; D009247:NADH, NADPH Oxidoreductases; C431909:tumor-associated NADH oxidase