Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy*
  • Beclin-1
  • Cannabidiol
  • Cannabinoids / chemistry*
  • Cannabinol / chemistry
  • Cell Death
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / chemistry
  • Dronabinol / chemistry
  • Drug Combinations
  • Humans
  • Male
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Neoplasms / metabolism
  • Plant Extracts / chemistry
  • Proto-Oncogene Proteins B-raf / metabolism
  • Skin Neoplasms / metabolism
  • Temozolomide
  • ras Proteins / metabolism

Substances

  • AMBRA1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Cannabinoids
  • Drug Combinations
  • Membrane Proteins
  • Plant Extracts
  • Cannabidiol
  • Dacarbazine
  • Dronabinol
  • Cannabinol
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • ras Proteins
  • nabiximols
  • Temozolomide