Melanosomal Damage in Normal Human Melanocytes Induced by UVB and Metal Uptake—A Basis for the Pro‐oxidant State of Melanoma^†

Abstract

Melanins are ubiquitous catecholic pigments, formed in organelles called melanosomes within melanocytes, the function of which is to protect skin against harmful effects of UV radiation. Melanosomes within melanoma cells are characteristically abnormal, with fragmented melanin and disrupted membranes. We hypothesize that the disruption of melanosomal melanin might be an early event in the etiology and progression of melanoma, leading to increased oxidative stress and mutation. In this report, we examine the effect of a combination of UV treatment and metal ion exposure on melanosomes within melanocytes, as well as their ability to act as pro-oxidants in ex situ experiments, and assay the effects of this treatment on viability and cell cycle progression. UVB exposure causes morphologic changes of the cells and bleaching of melanosomes in normal melanocytes, both significantly enhanced in Cu(II) and Cd(II)-treated cells, as observed by microscopy. The promoted bleaching by Cu(II) is due to its ability to redox cycle under oxidative conditions, generating reactive oxygen species; verified by the observed enhancement of hydroxyl radical generation when isolated melanosomes were treated with both Cu(II) ions and UVB, as assayed by DNA clipping. Single-dose UVB/Cu treatment does not greatly affect cell viability or cell cycle progression in heavily pigmented cells, but did so in an amelanotic early stage melanoma cell line.

Melanoma Epidemiology and Prevention

“…However, exposure to Cr(VI) resulted in morphological changes, aneuploidy was detected, and when cells from primary colonies were replated, secondary colonies formed. Additionally, exposure of human melanocytes to UVR and some metals causes bleaching of melanosomes and a pro-oxidant state [83]. Other physical evidence suggests a role in melanomagenesis as a wide variety of insecticides, PCBs, and metals (including chromium) have been identified bound to melanin [211].…”

Reactive Oxygen Species in the Biology of Melanoma

“…The human melanocyte is continuously exposed to reactive biochemical species, but is finely tuned via the intrinsic antioxidant and radical properties of melanin to suppress the build-up of an altered redox phenotype. Meyskens et al propose that this control is lost during the development of www.intechopen.com melanoma (Meyskens et al, 2001), moreover they hypothesize that the disruption of melanosomal melanin might be an early event in the etiology of melanoma, leading to increased oxidative stress and mutation (Gidanian et al, 2008). Sunlight exposure is the major cause of skin cancers, including melanoma.…”

Antioxidant Defense and UV-Induced Melanogenesis: Implications for Melanoma Prevention

“…UVR-mediated abnormality of melanogenic responses may result in cytotoxicity and mutagenicity, particularly in lightly pigmented melanocytes, that could contribute to malignant transformation of melanocytes (Baldea et al, 2009;Marrot et al, 2005;Riley, 2003;Slominski et al, 2004). Development of melanoma could also be associated with aggravation of melanogenesis in the melanocytes having disrupted melanosomes leading to leakage of melanin, which can further damage the cells through oxidative products (Gidanian et al, 2008;Sarangarajan & Apte, 2006). The melanin was demonstrated to significantly augment process of UVA-generated ROS and oxidative DNA damage probably responsible for melanomagenesis in Xeroderma pigmentosum patients, which exhibited impaired NER (H.T.…”