Nitric oxide and endothelin-1,2 in actinic keratosis and basal cell carcinoma:: changes in nitric oxide/endothelin ratio

Background Nitric oxide (NO) is an inorganic free radical gas which has cytostatic/cytotoxic actions in tumoral tissues, including gynecologic, breast, and colon cancer. Nitric oxide is also a multifunctional signaling molecule active in many cells of the body, including endothelial cells, macrophages, monocytes, hepatocytes, mast cells, osteoblasts, and astrocytes. Endothelin-1 (ET-1) is a 21-amino acid peptide that stimulates the proliferation of vascular smooth muscle cells, fibroblasts, and keratinocytes, and plays a role in the expression of proto-oncogenes (c-myc, c-fos), which precedes cell proliferation. Similar to NO, ET is secreted by different cell types, including macrophages, monocytes, hepatocytes, endothelial cells, vascular smooth muscle cells, and various tumor cells. Elevated ET-1 levels are observed in pulmonary, hepatocellular, and prostate cancers. Actinic keratosis (AK) and basal cell carcinoma (BCC) are common skin tumors with accentuated hyperkeratinization, hyperpigmentation, and keratinocyte proliferation. Aim To investigate plasma NOx (nitrite/nitrate - the end products of NO metabolism), ET, and the NOx/ET ratio in patients with AK and BCC in comparison with healthy controls. Methods NOx, ET, and the NOx/ET ratio were measured in 13 patients with AK, 12 patients with BCC, and in 16 healthy controls. Results Data analysis indicated a significant increase in plasma NOx, ET, and NOx/ET values in BCC patients in comparison with controls (P<0.001, P<0.05 and P<0.001, respectively). Plasma ET levels in AK were also increased in comparison with controls (P< 0.001). When the two study groups (AK and BCC) were compared, a significant increase (P<0.001) in the NOx/ET ratio in BCC was found. Conclusions The increased plasma ET and NO, levels in AK and, especially, BCC are probably the result of and/or reason for the accentuated hyperkeratinization, hyperpigmentation, and keratinocyte proliferation. The increased production of ET and NO by keratinocytes may function as growth and cytotoxic factors and potential mitogens, and may accelerate further proliferation of these skin tumors. In addition, the increased NOx/ET ratio probably reflects a disturbed equilibrium between these two substances, leading to cell damage and tumor promotion and proliferation.