Journal Article

Exploiting Cannabinoid-Induced Cytotoxic Autophagy to Drive Melanoma Cell Death

Babatunde, Fiyinfoluwa, Lovat, Penny E., McKee, Christopher S., Lopez-Valero, Israel, Lorente, Mar, Velasco, Guillermo, Armstrong, Jane L., Corazzari, Marco, Hill, David S., Hernandez-Tiedra, Sonia, Redfern, Christopher P.F., Eleni Anagnostou, Maria

2015

Overview

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.

• Publisher: Elsevier Inc,Elsevier Limited
• Subject: 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 / ras Proteins - metabolism / Skin Neoplasms - metabolism / Temozolomide