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

Chen Yang; Mark Stephen Rybchyn; Warusavithana Gunawardena Manori De Silva; Jim Matthews; Katie Marie Dixon; Andrew J. A. Holland; Arthur David Conigrave; Rebecca Sara Mason

doi:10.3390/ijms24054921

International Journal of Molecular Sciences (Mar 2023)

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

Chen Yang,
Mark Stephen Rybchyn,
Warusavithana Gunawardena Manori De Silva,
Jim Matthews,
Katie Marie Dixon,
Andrew J. A. Holland,
Arthur David Conigrave,
Rebecca Sara Mason

Affiliations

Chen Yang: School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia
Mark Stephen Rybchyn: School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia
Warusavithana Gunawardena Manori De Silva: School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia
Jim Matthews: Sydney Informatics Hub, University of Sydney, Sydney, NSW 2008, Australia
Katie Marie Dixon: School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia
Andrew J. A. Holland: 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
Arthur David Conigrave: School of Life and Environmental Sciences, Charles Perkins Centre (D17), University of Sydney, Sydney, NSW 2006, Australia
Rebecca Sara Mason: School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia

DOI: https://doi.org/10.3390/ijms24054921
Journal volume & issue: Vol. 24, no. 5
p. 4921

Abstract

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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 p 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 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.

Published in International Journal of Molecular Sciences

ISSN: 1661-6596 (Print); 1422-0067 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General); Science: Chemistry
Website: http://www.mdpi.com/journal/ijms

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