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Abstract The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.

Abstract The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.

Summary We have previously observed that melanocytes produce nitric oxide in response to ultraviolet radiation and lipopolysaccharide and in this study have examined how these responses are affected by α-melanocyte-stimulating hormone. Nitric oxide production by cultured cells was measured electrochemically in real time using an ISO-nitric oxide sensor probe. B16 mouse melanoma cells released nitric oxide in response to lipopolysaccharide and the effects were enhanced in cells that had been grown in the presence of 10-11-10-9 M α-melanocyte-stimulating hormone prior to stimulation. At concentrations in excess of 10-9 M α-melanocyte-stimulating hormone decreased nitric oxide production. Preincubation with lipopolysaccharide, a well-known inducer of inducible nitric oxide synthase, also increased nitric oxide production but this response was reduced by α-melanocyte-stimulating hormone. α-Melanocyte-stimulating hormone also increased the levels of nitric oxide produced in response to ultraviolet radiation (20–100 mJ per cm2) in B16 cells. The same effect was seen in human melanocytes and as this was inhibited by aminoguanidine would appear to involve an induction of inducible nitric oxide synthase. Reverse transcription–polymerase chain reaction showed that melanocytic cells express inducible nitric oxide synthase mRNA. Western blotting analysis and immunocytochemistry confirmed the presence of inducible nitric oxide synthase protein in B16 cells and FM55 human melanoma cells and that the levels were increased in response to α-melanocyte-stimulating hormone. α-Melanocyte-stimulating hormone, however, decreased inducible nitric oxide synthase protein expression, which occurred in response to lipopolysaccharide. These results suggest that α-melanocyte-stimulating hormone regulates nitric oxide production in melanocytic cells by modulating the induction of inducible nitric oxide synthase. Additional experiments showed that nitric oxide increased melanin production by B16 cells and human melanocytes. This is in keeping with a melanogenic role for nitric oxide but whether its production by melanocytes in response to α-melanocyte-stimulating hormone is associated with such a role or whether it has some other significance relating to melanocyte differentiation or in mediating immunomodulatory actions of α-melanocyte-stimulating hormone remains to be seen. [ABSTRACT FROM AUTHOR]

Betulin is a principal component of birch bark and is known to possess a broad range of biological activities, including antiinflammatory, antiviral and anticancer actions. The present study was carried out in vitro to clarify the influence of betulin on melanocortin (MC) receptor-ergic signalling by using COS-7 cells transfected with corresponding human MC receptor DNA. The results showed that betulin binds to the human melanocortin MC1, three to five receptors with selectivity to the MC1 subtype (K(i) value 1.022 +/- 0.115 microM). Betulin binds to the MC receptors with the following potency order-MC > MC3 > MC5 > MC4. Betulin itself does not stimulate cAMP generation, however, it slightly antagonizes alpha-melanocyte-stimulating hormone (alpha-MSH)-induced cAMP accumulation in the mouse melanoma cell line B16-F1. As a water-insoluble substance, betulin was dissolved in DMSO therefore DMSO competition with the labelled ligand NDP-MSH for the binding to the MC receptors was tested in the identical experimental set-up. We found that DMSO competes for binding to all the MC receptor subtypes, at 20% concentration and above. Selectivity for one or another receptor subtype was not observed. We have demonstrated for the first time, the ability of the plant compound betulin to bind to the MC receptors. One may suggest MC receptor MC1 subtype as the essential target for the antimelanoma action of betulin and its structurally close molecules such as betulinic acid. Moreover, we have found a new non-peptide small molecule MC mimetic, that is betulin. Thus, we report a new chemical motif for the binding to the MC receptors that could be used as a template for the search of more selective MC mimetics.