title: Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death.
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.
authors: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK; Faculty of Applied Sciences, University of Sunderland, Sunderland, UK.
authors: Jane L
authors: JL
authors: Armstrong
authors: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors: David S
authors: DS
authors: Hill
authors: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors: Christopher S
authors: CS
authors: McKee
authors: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
authors: Sonia
authors: S
authors: Hernandez-Tiedra
authors: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
authors: Mar
authors: M
authors: Lorente
authors: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
authors: Israel
authors: I
authors: Lopez-Valero
authors: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors: Maria
authors: M
authors: Eleni Anagnostou
authors: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors: Fiyinfoluwa
authors: F
authors: Babatunde
authors: Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
authors: Marco
authors: M
authors: Corazzari
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors: Christopher P F
authors: CPF
authors: Redfern
authors: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
authors: Guillermo
authors: G
authors: Velasco
authors: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK. Electronic address: penny.lovat@ncl.ac.uk.
authors: Penny E
authors: PE
authors: Lovat
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D002185:Cannabidiol; D002186:Cannabinoids / Q000737:chemistry*; D002187:Cannabinol / Q000737:chemistry; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000737:chemistry; D013759:Dronabinol / Q000737:chemistry; D004338:Drug Combinations; D006801:Humans; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism; D000077204:Temozolomide; D018631:ras Proteins / Q000378:metabolism
chemical_list: C553334:AMBRA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D002186:Cannabinoids; D004338:Drug Combinations; D008565:Membrane Proteins; D010936:Plant Extracts; D002185:Cannabidiol; D003606:Dacarbazine; D013759:Dronabinol; D002187:Cannabinol; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; C587251:nabiximols; D000077204:Temozolomide