Sunscreen currently provides a way to prevent development of skin cancer caused by sun exposure by blocking UV rays from reaching and damaging skin cells (1
). However, despite the use of sunscreen, melanoma incidence and mortality rates continue to rise (1
). UV damage accounts for ~30% of melanomas and an additional ~10% are inherited in families; for the remaining ~70%, the cause remains uncertain (1
). Therefore, new novel approaches are needed to augment existing strategies for the prevention of this disease (1
). With more than 1 billion spent on sunscreen every year in the United States, the market for skin cancer prevention is enormous and continues to grow (43
). Therefore, addition of agents such as ISC-4 to sunscreens, body lotions or creams could have a profound impact on this existing market for preventing melanoma.
Topical or localized treatments, such as those being proposed for ISC-4, could permit the use of high local concentrations with minimal toxicity and beuseful for treating cutaneous lesions not amenable to surgicalremoval or other currently available approaches (44
). Topical treatment could also allow transdermal delivery of high concentrations of the agent to the melanocytic lesion while minimizing toxicity and other unintended off-target effects associated with systemic administration (45
). It is therefore clear that effective prevention and treatment options for melanocytic lesions are urgently needed and that a topical ISC-4 formulation might be a component of this solution.
Currently, surgical excision is the mainstay for eliminating early melanocytic lesions or preventing development into more aggressive cancer (9
); however, topical ISC-4 treatment could potentially be an adjunct or alternative to surgery for some patients (46
). Targeting signaling cascades, such as the Akt3 pathway involved in early melanoma development by decreasing inhibitory MAP kinase pathway activity and deregulating apoptosis would be the goal of targeted chemoprevention; however, normal cells also utilize these same pathways (47
). Therefore, the challenge would be to develop a chemopreventive agent that exerts maximal effect on cancer cells with minimal effect on normal ones. ISC-4 fulfills these criteria since it has negligible effects on normal cells in culture, did not cause obvious damage to keratinocytes, fibroblasts, skin architecture or organ function, thereby supporting its potential for topical use.
Naturally occurring chemicals can be useful for preventing cancer. Plants are one source for these agents providing many nutrients, antioxidants, phyto-chemicals and minerals such as selenium (19
). Isothiocyanates from which ISC-4 was developed are naturally occurring phytochemicals found in cruciferous vegetables with many anti-cancer properties. Among the most well studied isothiocyanates are phenethyl isothiocyanate, sulforaphane, indole-3-carbinol (2
). Selenium is an essential mineral element present in many dietary sources and its deficiency has been reported to occur in certain cancers including melanoma (25
). Dietary selenium supplementation above the recommended daily allowance has been found to lower incidence of some cancers, particularly prostate cancer (50
). The exact mechanisms for the anti-cancer effects of selenium are not fully known (14
), but may involve antioxidant protection, altered carcinogen metabolism, decreased inflammation, enhanced immune protection, induction of cell cycle arrest and apoptosis, and inhibition of tumor invasion (16
). Since both isothiocyanates and selenium possess independent anti-cancer properties, incorporating selenium structurally into PBITC has been shown to enhance efficacy of ISC-4 for inhibiting cancer (11
) and for preventing cutaneous melanocytic lesion development in this study.
Prior reports have shown that control compounds structurally similar to ISC-4 had little effect on melanoma cell survival; therefore, the tumor inhibitory effects mediated by ISC-4 are dependent on the structure of the compound and the presence of selenium in this molecule, which confers its enhanced chemopreventive activity (16
). Compared with the chemopreventive effects of other selenium-containing agents, ISC-4 performs a unique role in melanoma by targeting Akt3 signaling to promote apoptosis and prevent tumor development with negligible toxicity at biologically effective topical doses. The longer alkyl chain length increases lipophilicity and thereby cellular uptake (51
). Selenium in turn enhances the potency for Akt3 inhibition (17
). Efficacy for inhibiting cutaneous melanocytic lesion development in this study suggests that ISC-4 can permeate the skin easily reaching the cancer cells where it performs its inhibitory role. Therefore, ISC-4 represents a promising adjunct to currently available chemopreventive agents or for use on cutaneous melanomas for which surgical excision is not an option.
In conclusion, this study demonstrates the utility of topical ISC-4 for preventing 80–90% of cutaneous melanocytic lesion development in preclinical models by targeting the Akt3 signaling cascade. Thus, topical ISC-4 has potential to delay or slow melanocytic lesion or melanoma development in preclinical models and could impact melanoma incidence if similar results are observed in humans.