Do TRPV1 antagonists increase the risk for skin tumourigenesis? A collaborative in vitro and in vivo assessment

• Published in: Cell biology and toxicology Vol. 34; no. 2; pp. 143 - 162
• Main Authors: Park, Miyoung, Naidoo, Anita A., Burns, Angie, Choi, Jin Kyu, Gatfield, Kelly M., Vidgeon-Hart, Martin, Bae, Il-Hong, Lee, Chang Seok, Choi, Gyeyoung, Powell, Andrew J., Park, Young-Ho, Fagg, Rajni
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.04.2018; Springer Nature B.V
• Subjects: Acrylamides - toxicity; AKT protein; Animals; Antagonists; Anthracenes - toxicity; Biochemistry; Biomedical and Life Sciences; Bridged Bicyclo Compounds, Heterocyclic - toxicity; Capsaicin - analogs & derivatives; Capsaicin - toxicity; Capsaicin receptors; Carcinogenesis; Carcinogens; Cell Biology; Cell Line; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cocarcinogenesis; Data processing; Drug development; Epidermal growth factor receptors; Female; Humans; Hypotheses; In vivo methods and tests; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - metabolism; Keratinocytes - pathology; Life Sciences; Mice; Mice, Hairless; Molecular modelling; Original Article; Pharmacology; Pharmacology/Toxicology; Piperidines - toxicity; Primary Cell Culture; Proteins; Pyridines - toxicity; Pyrrolidines - toxicity; Risk; Signal transduction; Signaling; Skin; Skin cancer; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Telomerase; Topical application; TOR protein; Transient receptor potential proteins; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - genetics; Tumorigenesis; Tumors; Urea - analogs & derivatives; Urea - toxicity; Skin tumour; TRPV1; Human keratinocytes; EGFR/Akt/mTOR
• ISSN: 0742-2091; 1573-6822
• DOI: 10.1007/s10565-017-9407-8

A recent hypothesis suggesting that the pharmacological target TRPV1 (transient receptor potential vanilloid subfamily, member 1) may function as a tumour suppressor, which potentially impacts the development of TRPV1 antagonist therapeutics for a range of conditions. However, little is known about the long-term physiologic effects of TRPV1 blockade in the skin. In vitro and in vivo studies suggested that the potent TRPV1 competitive antagonist AMG-9810 promoted proliferation in N/TERT1 cells (telomerase-immortalised primary human keratinocytes 1) and tumour development in mouse skin that was mediated through EGFR/Akt/mTOR signalling. We attempted to reproduce the reported in vitro and in vivo findings to further explore this hypothesis to understand the underlying mechanism and the risk associated with TRPV1 antagonism in the skin. In vitro proliferation studies using multiple methods and topical application with AMG-9810 and structurally similar TRPV1 antagonists such as SB-705498 and PAC-14028 were performed. Although we confirmed expression of TRPV1 in primary human epidermal keratinocytes (HEKn) and spontaneously immortalised human keratinocytes (HaCaT), we were unable to demonstrate cell proliferation in either cell type or any clear evidence of increased expression of proteins in the EGFR/Akt/mTOR signalling pathway with these molecules. We were also unable to demonstrate skin tumour promotion or underlying molecular mechanisms involved in the EGFR/Akt/mTOR signalling pathway in a single-dose and two-stage carcinogenesis mouse study treated with TRPV1 antagonists. In conclusion, our data suggest that inhibiting the pharmacological function of TRPV1 in skin by specific antagonists has not been considered to be indicative of skin tumour development.