Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death

Armstrong, Jane, Hill, DS, McKee, CS, Hernandez-Tiedra, S, Lorente, M, Lopez-Valero, I, Eleni Anagnostou, M, Babatunde, F, Corazzari, M, Redfern, CP, Velasco, G and Lovat, PE (2015) Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death. Journal Of Investigative Dermatology, 135 (6). pp. 1629-1637. ISSN 0022-202X

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Abstract

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 Δ9-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.

Item Type: Article
Subjects: Sciences
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Nursing and Health Sciences
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences
Depositing User: Paula Normington
Date Deposited: 16 Oct 2015 08:40
Last Modified: 19 Feb 2020 16:15
URI: http://sure.sunderland.ac.uk/id/eprint/5472
ORCID for Jane Armstrong: ORCID iD orcid.org/0000-0002-5822-0597

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