gw-1000 and Neoplasm-Metastasis

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.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Cannabidiol; Cannabinoids; Cannabinol; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dacarbazine; Dronabinol; Drug Combinations; Humans; Male; Melanoma; Membrane Proteins; Mice; Mice, Nude; Microscopy, Confocal; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Plant Extracts; Proto-Oncogene Proteins B-raf; ras Proteins; Skin Neoplasms; Temozolomide