The CaSR Modulator NPS-2143 Reduced UV-Induced DNA Damage in Skh:hr1 Hairless Mice but Minimally Inhibited Skin Tumours

  • Int J Mol Sci. 2023 Mar 3;24(5):4921. doi: 10.3390/ijms24054921.
Chen Yang  1 ,  Mark Stephen Rybchyn  1  2 ,  Warusavithana Gunawardena Manori De Silva  1 ,  Jim Matthews  3 ,  Katie Marie Dixon  1 ,  Andrew J A Holland  4 ,  Arthur David Conigrave  5 ,  Rebecca Sara Mason  1  5
Affiliations
  • 1. School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
  • 2. School of Chemical Engineering, University of New South Wales, Sydney, NSW 2033, Australia.
  • 3. Sydney Informatics Hub, University of Sydney, Sydney, NSW 2008, Australia.
  • 4. Douglas Cohen Department of Paediatric Surgery, The Children's Hospital at Westmead Clinical School, The Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2145, Australia.
  • 5. School of Life and Environmental Sciences, Charles Perkins Centre (D17), University of Sydney, Sydney, NSW 2006, Australia.
PMID: 36902353 DOI: 10.3390/ijms24054921
Abstract

The calcium-sensing receptor (CaSR) is an important regulator of epidermal function. We previously reported that knockdown of the CaSR or treatment with its negative allosteric modulator, NPS-2143, significantly reduced UV-induced DNA damage, a key factor in skin Cancer development. We subsequently wanted to test whether topical NPS-2143 could also reduce UV-DNA damage, immune suppression, or skin tumour development in mice. In this study, topical application of NPS-2143 (228 or 2280 pmol/cm2) to Skh:hr1 female mice reduced UV-induced cyclobutane pyrimidine dimers (CPD) (p < 0.05) and oxidative DNA damage (8-OHdG) (p < 0.05) to a similar extent as the known photoprotective agent 1,25(OH)2 vitamin D3 (calcitriol, 1,25D). Topical NPS-2143 failed to rescue UV-induced immunosuppression in a contact hypersensitivity study. In a chronic UV photocarcinogenesis protocol, topical NPS-2143 reduced squamous cell carcinomas for only up to 24 weeks (p < 0.02) but had no Other effect on skin tumour development. In human keratinocytes, 1,25D, which protected mice from UV-induced skin tumours, significantly reduced UV-upregulated p-CREB expression (p < 0.01), a potential early anti-tumour marker, while NPS-2143 had no effect. This result, together with the failure to reduce UV-induced immunosuppression, may explain why the reduction in UV-DNA damage in mice with NPS-2143 was not sufficient to inhibit skin tumour formation.

Keywords
1a,25-dihydroxyvitamin D3 (1,25D); 8-hydroxy-2′–deoxyguanosine (8-OHdG); calcium sensing receptor (CaSR); cyclic AMP response element binding factor (CREB); cyclobutane pyrimidine dimer (CPD); photocarcinogenesis; photoprotection; squamous cell carcinoma (SCC); ultraviolet radiation (UV).
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