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Do TRPV1 antagonists increase the risk for skin tumourigenesis? A collaborative in vitro and in vivo assessment.
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.
Afiliación
  • Park M; Vital Beautie Research Institute, AmorePacific Corporation R&D Centre, Yongin, South Korea. mypark@amorepacific.com.
  • Naidoo AA; Department of Investigative Safety and Drug Metabolism, GlaxoSmithKline Research and Development, Ware, Hertfordshire, SG12 0DP, UK. anita.a.naidoo@gsk.com.
  • Burns A; Department of Toxicology and Drug Metabolism, GlaxoSmithKline Research and Development, Ware, Hertfordshire, SG12 0DP, UK.
  • Choi JK; Medical Beauty QA Team, Aestura, Anseong, South Korea.
  • Gatfield KM; Department of Screening, Profiling and Mechanistic Biology, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire, SG1 2NY, UK.
  • Vidgeon-Hart M; Department of Investigative Safety and Drug Metabolism, GlaxoSmithKline Research and Development, Ware, Hertfordshire, SG12 0DP, UK.
  • Bae IH; Vital Beautie Research Institute, AmorePacific Corporation R&D Centre, Yongin, South Korea.
  • Lee CS; Vital Beautie Research Institute, AmorePacific Corporation R&D Centre, Yongin, South Korea.
  • Choi G; Vital Beautie Research Institute, AmorePacific Corporation R&D Centre, Yongin, South Korea.
  • Powell AJ; Department of Screening, Profiling and Mechanistic Biology, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire, SG1 2NY, UK.
  • Park YH; Vital Beautie Research Institute, AmorePacific Corporation R&D Centre, Yongin, South Korea.
  • Fagg R; Department of Translation Platform Project Specialists, GlaxoSmithKline Research and Development, Ware, Hertfordshire, SG12 0DP, UK.
Cell Biol Toxicol ; 34(2): 143-162, 2018 04.
Article en En | MEDLINE | ID: mdl-28815372
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Queratinocitos / Proliferación Celular / Canales Catiónicos TRPV Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Cell Biol Toxicol Asunto de la revista: TOXICOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Corea del Sur Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Queratinocitos / Proliferación Celular / Canales Catiónicos TRPV Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Cell Biol Toxicol Asunto de la revista: TOXICOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Corea del Sur Pais de publicación: Suiza