Melanoma inhibition by cyclooxygenase inhibitors: role of interleukin-6 suppression, a putative mechanism of action, and clinical implications.
Melanoma progression is often associated with supranormal levels of interleukin-6 (IL-6). Il-6 is an important growth factor for many cases of melanoma. A recent case report by Lejeune et al. [Melanoma Res 2006;16:263-265] of remission of an advanced melanoma during treatment with the cyclooxygenase, (COX) inhibitor rofecoxib can be explained by rofcoxib-mediated lowering of tumor-produced Il-6. Several examples of rofecoxib's ability to lower Il-6 in humans have been published recently in other settings, and many reports indicate that other commonly used COX inhibitors like aspirin, diclofenac, etodolac, indomethacin, naproxen, and many others, also lower Il-6 in humans. These studies are reviewed. The likely mechanism of COX inhibition leading to Il-6 lowering is due to the tendency for Il-6 levels to be controlled by intracellular cyclic adenosine monophosphate (cAMP). Adenylate cyclase is the rate-limiting enzyme in cAMP synthesis. Because adenylate cyclase activity is allosterically enhanced when it binds prostaglandin E, the latter increases Il-6. COX inhibition lowers prostaglandin E levels. This lowers intracellular cAMP levels. Lower cAMP results in lower Il-6 synthesis, lower levels of a required growth factor. Controlled studies are needed to define the role of COX inhibitors in melanoma treatment.
Department of Psychiatry, University of Vermont, Burlington, VT 05401, USA. rekast@email.com
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D000242:Cyclic AMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000242:Cyclic AMP; D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D011451:Prostaglandin-Endoperoxide Synthases; D000093242:Interleukin-6 Inhibitors