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Exploiting Cannabinoid-Induced Cytotoxic Autophagy to Drive Melanoma Cell Death

Lookup NU author(s): Dr Jane Renwick, Dr David Hill, Christopher McKee, Maria Anagnostou, Fiyinfoluwa Babatunde, Dr Chris Redfern, Professor Penny Lovat

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

Although the global incidence of cutaneous melanoma is increasing, survival rates for patients with metastatic disease remain o10%. 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 autophagymediated apoptosis of melanoma cells, suggesting that cytotoxic autophagy induction with Sativex warrants clinical evaluation for metastatic disease.


Publication metadata

Author(s): Armstrong JL, Hill DS, McKee CS, Hernandez-Tiedra S, Lorente M, Lopez-Valero I, Anagnostou ME, Babatunde F, Corazzari M, Redfern CPF, Velasco V, Lovat PE

Publication type: Article

Publication status: Published

Journal: Journal of Investigative Dermatology

Year: 2015

Volume: 135

Issue: 6

Pages: 1629-1637

Print publication date: 01/06/2015

Online publication date: 10/02/2015

Acceptance date: 21/01/2014

ISSN (print): 0022-202X

ISSN (electronic): 1523-1747

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/jid.2015.45

DOI: 10.1038/jid.2015.45


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