1α,25(OH)2-Vitamin D and a Nongenomic Vitamin D Analogue Inhibit Ultraviolet Radiation–Induced Skin Carcinogenesis

Abstract

Exposure to ultraviolet radiation (UVR) can lead to a range of deleterious responses in the skin. An important form of damage is the DNA photolesion cyclobutane pyrimidine dimer (CPD). CPDs can be highly mutagenic if not repaired prior to cell division and can lead to UV-induced immunosuppression, making them potentially carcinogenic. UVR exposure also produces vitamin D, a prehormone. Different shapes of the steroid hormone 1a,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] can produce biological responses through binding either to its cognate nuclear receptor (VDR) to regulate gene transcription or to the VDR associated with plasma membrane caveolae to produce, via signal transduction, nongenomic physiologic responses. Here, we show that both 1,25(OH) 2 D 3 and 1a,25(OH) 2 -lumisterol (JN), a conformationally restricted analogue that can generate only nongenomic responses, are effective inhibitors of UV damage in an immunocompetent mouse (Skh:hr1) model susceptible to UV-induced tumors. Both 1,25(OH) 2 D 3 and JN significantly reduced UVR-induced CPD, apoptotic sunburn cells, and immunosuppression. Furthermore, these compounds inhibited skin tumor development, both papillomas and squamous cell carcinomas, in these mice. The observed reduction of these UV-induced effects by 1,25 (OH) 2 D 3 and JN suggests a role for these compounds in prevention against skin carcinogenesis. To the best of our knowledge, this is the first comprehensive report of an in vivo long-term biological response generated by chronic dosing with a nongenomic-selective vitamin D steroid.

Ultraviolet Radiation Suppresses Obesity and Symptoms of Metabolic Syndrome Independently of Vitamin D in Mice Fed a High-Fat Diet

“…This dose of 1,25(OH) 2 D was previously reported to not induce hypercalcemia (19). All topical reagents were diluted with a vehicle consisting of ethanol, propylene glycol, and water (2:1:1) (20).…”

CYP11A1 in skin: An alternative route to photoprotection by vitamin D compounds

“…Interest in the role of the hormonally active form of vitamin D 3 , 1,25-dihydroxyvitamin D 3 (1,25D), also known as calcitriol, in reducing UVR-induced or chemically-induced skin tumors is becoming more widespread [1][2][3]. Vitamin D 3 is produced in skin through the actions of UVR (290-315 nm) on 7-dehydrocholesterol to produce pre-vitamin D, which then thermally isomerizes to vitamin D 3 [4].…”

“…It is widely known that excessive DNA damage in skin cells exposed chronically to UVR may initiate mutations, contribute to systemic immunosuppression, and result in skin tumorigenesis [3,[22][23][24][25]. Our group has demonstrated that 1,25D reduces UVRinduced DNA damage, including cyclobutane pyrimidine dimers (CPDs), the most common of which are thymine dimers, in human keratinocyte cultures [26], mouse skin and human skin in vivo [3,[27][28][29] or human skin explants [30], and it also reduces UVRinduced immune suppression [25,27,28] and tumor growth in UV irradiated hairless mice [3].…”

Vitamin D Supplementation Does Not Improve the Severity or the Resolution of Ultraviolet B-Induced Acute Erythema

“…Calcitriol [1α,25-dihydroxyvitamin D 3 or 1,25(OH) 2 D 3 ] may enhance keratinocyte [8][9][10][11][12][13] , melanocyte [13] and fibroblast [10,13] survival after UVR exposure by reducing UV-induced promutagenic DNA damage like cyclobutane pyrimidine dimers [8][9][10][11][12][13] , 8-oxo-7,8-dihydro-2-deoxyguanosine [9,14] , 3-nitrotyrosine, and 8-nitroguanosine [9,15,16] , which are mutagenic and are markers of inflammation and carcinogenesis. Moreover, 1,25(OH) 2 D 3 could also influence the upregulation of p53, allowing improvement of DNA repair [13] .…”