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J Invest Dermatol. 2015 Jun;135(6):1629-1637. doi: 10.1038/jid.2015.45. Epub 2015 Feb 10.

Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death.

Author information

1
Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK; Faculty of Applied Sciences, University of Sunderland, Sunderland, UK.
2
Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
3
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
4
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
5
Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
6
Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
7
Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK. Electronic address: penny.lovat@ncl.ac.uk.

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 Δ(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.

PMID:
25674907
DOI:
10.1038/jid.2015.45
[Indexed for MEDLINE]
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