Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 135, Issue 6, Pages 1629-1637Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2015.45
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Funding
- JGW Patterson Foundation
- British Skin Foundation
- Newcastle Healthcare Charity
- North Eastern Skin Research Fund
- Health Sciences and Wellbeing Beacon (University of Sunderland)
- Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos iii (MINECO/ISCiii)
- European Regional Development Fund ((ERF/FEDER)) [PS09/01401, PI12/02248]
- Fundacion Mutua Madrilena
- Fundacion TELEMARATO
- GW Pharmaceutical
- Comunidad de Madrid
- Spanish Ministry of Education and Science
- Associazione Italiana per la Ricerca sul Cancro
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/L002000/1] Funding Source: researchfish
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Although the global incidence of cutaneous melanoma is increasing, survival rates for patients with metastatic disease remain <10%. Novel treatment strategies are therefore urgently required, particularly for patients bearing BRAF/NRAS wild-type tumors. Targeting autophagy is a means to promote cancer cell death in chemotherapy-resistant tumors, and the aim of this study was to test the hypothesis that cannabinoids promote autophagy-dependent apoptosis in melanoma. Treatment with Delta(9)-Tetrahydrocannabinol (THC) resulted in the activation of autophagy, loss of cell viability, and activation of apoptosis, whereas cotreatment with chloroquine or knockdown of Atg7, but not Beclin-1 or Ambra1, prevented THC-induced autophagy and cell death in vitro. Administration of Sativex-like (a laboratory preparation comprising equal amounts of THC and cannabidiol (CBD)) to mice bearing BRAF wild-type melanoma xenografts substantially inhibited melanoma viability, proliferation, and tumor growth paralleled by an increase in autophagy and apoptosis compared with standard single-agent temozolomide. Collectively, our findings suggest that THC activates noncanonical autophagy-mediated apoptosis of melanoma cells, suggesting that cytotoxic autophagy induction with Sativex warrants clinical evaluation for metastatic disease.
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