NF-kappaB, macrophage migration inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the acetaminophen- and NSAID-prevention of the ovarian cancer.
Recent epidemiological studies indicated risk reductions in ovarian cancer with consumption of acetaminophen or non-steroid anti-inflammatory drugs. Until now, there is not a systematic analysis, why these agents may reduce risk of ovarian cancer, as it has been performed to explain aspirin-reduction of colon cancer risk. This review tries to explain molecular mechanisms pertinent to acetaminophen- and NSAID-reduction of ovarian cancer. It is proposed that the major mechanism by these anti-inflammatory agents is a shared pathway dependent on the suppression of NF-kappaB activity, which may subsequently decrease transcription of growth factors, chemokines and proteases such as COX-2, VEGF, IL-8/CXCL8, MCP-1/CCL-2, MIP1alpha/CCL-3, tPA and uPA, which are shown to be elevated in ovarian carcinoma, and which play diverse roles such as inducing angiogenesis, invasion, autocrine growth loops and resistance to apoptosis. Besides these, specific mechanisms of action can be attributed to acetaminophen-reduction of ovarian cancer risk via I. Induction of specific reproductive atrophy due its sex-steroid resembling phenolic ring; II. Reduction of glutathione pools due to its NAPQI metabolite, which may play an important role for sterilizing pre-malignant ovarian lesions, since they are shown to lack proper levels of glutathione; III. Inhibition of tautomerization activity of MIF (macrophage migration inhibitory factor), which is shown to be released from ovarian cancer, and which is necessary for proper ovulation; IV. Inhibition of cytokine-induced and endothelia-origined cyclooxygenases. Except the chemosensitization studies, acetaminophen and NSAIDs should be investigated in animal models to test likely benefits in ovarian cancer, since most of their activity may origin from intervening with the cancer growth-stimulating inflammatory stimuli, rather than with the direct cellular toxicity.
Altinoz
M A
MA
Department of Neuroimmunology, Montreal Neurological Institute at McGill University, H3A2B4, Quebec, Canada. maltinoz@hotmail.com
Korkmaz
R
R
D000082:Acetaminophen / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007527:Isoenzymes / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology*; D008565:Membrane Proteins; D016328:NF-kappa B / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; D016328:NF-kappa B; D000082:Acetaminophen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C466421:cyclooxygenase-3; D005978:Glutathione