Carbon monoxide signalling reduces photocarcinogenesis in the hairless mouse.
Exposure of the skin of mice to UVA (320-400 nm) radiation has been shown to provide protection against the immunosuppressive effects of UVB (290-320 nm) radiation. The UVA protection was mediated via the UVA induction of the stress protein heme oxygenase-1, and its enzymatic product carbon monoxide (CO). Because UVB-induced immunosuppression is an accompanying and prerequisite feature of the promotion phase of photocarcinogenesis, the potential for immunoprotective CO to act as an anti-skin cancer agent was tested in this study. Groups of female albino Skh:hr-1 hairless mice were irradiated chronically with daily minimally erythemogenic doses of solar simulated UV radiation (SSUV) during a 10 week-period to induce photocarcinogenesis. The effect of repeated topical application of lotions containing a CO-releasing molecule (CORM-2; tricarbonyldichlororuthenium (II) dimer) at 250 or 500 microM, that had previously been shown in short-term experiments to provide photoimmune protection in mice, was measured. Tumor development was monitored for 29 weeks. Topical CORM-2 treatment was observed to reduce the acute and chronic inflammatory erythema reaction compared with control irradiated mice that did not receive CORM-2 lotions, and to reduce the chronic epidermal hyperplasia accompanying tumor outgrowth. The CORM-2 treatments provided a significant moderate inhibition of early tumor appearance dose-dependently, significantly reduced the average tumor multiplicity, increased the regression of established tumors dose-dependently, and inhibited the formation of large locally invasive tumors. The CORM-2 treatments also reduced the expression of immunosuppressive IL-10 in the uninvolved epidermis and dermis of tumor-bearing mice, and enhanced immunopotentiating epidermal IL-12 expression. Therefore CO signalling was revealed to have previously unrecognized anti-carcinogenic functions in the skin, consistent with a protective modulation of the epidermal cytokines. This is a novel observation that also implies that the UVA waveband that produces CO physiologically in exposed skin, might likewise be found to have an anti-photocarcinogenic action.
Allanson
Munif
M
Faculty of Veterinary Science, University of Sydney, Sydney, NSW, Australia.
Reeve
Vivienne E
VE
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism / Q000502:physiology*; D002273:Carcinogens / Q000528:radiation effects*; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000503:physiopathology / Q000517:prevention & control*; D047368:Tumor Burden; D014466:Ultraviolet Rays
D002273:Carcinogens; D007376:Interleukin-2; D016753:Interleukin-10; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1