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.

The use of cannabinoids as anticancer agents

“…Thus, THC binds cannabinoid receptors, which leads to the stimulation of sphingolipid synthesis de novo and the subsequent activation of an ER stress-related signaling route that involves the up-regulation of the transcriptional co-activator nuclear protein 1 (Nupr1, also named p8) and its effector the pseudo-kinase tribbles homolog 3 (TRIB3) (Armstrong et al, 2015;Blazquez et al, 2004;Carracedo et al, 2006a;Carracedo et al, 2006b;Galve-Roperh et al, 2000;Gomez del Pulgar et al, 2002;Velasco et al, 2012). The stimulation of this pathway promotes in turn autophagy via TRIB3-mediated inhibition of the AKT/ mTORC1 axis (Salazar et al, 2009;Salazar et al, 2013).…”

“…9 upstream of apoptosis in the mechanism of cannabinoid-induced cell death (Armstrong et al, 2015;Salazar et al, 2009;Vara et al, 2011).…”

“…The direct participation of the autophagy pathway in the antitumour action of cannabinoids has been clearly demonstrated in different types of cancer cells (namely, glioma, melanoma, pancreatic and hepatic cancer cells; (Armstrong et al, 2015;Carracedo et al, 2006a;Carracedo et al, 2006b;Salazar et al, 2009;Vara et al, 2011).…”

Cannabinoid pharmacology in cancer research: A new hope for cancer patients?

“…Other studies have shown the ability of cannabinoids to affect cellular signalling pathway/s essential for cell survival and growth Kogan, 2005). Some studies have also demonstrated and suggested the involvement of autophagy in the mechanism of cannabinoidinduced cytotoxicity (Armstrong et al 2015;Vara et al, 2011;McAllister et al, 2015).…”

The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids

“…This group went on to further demonstrate that CB 1 -selective and CB 2 -selective receptor agonists induced autophagic cell death in part through the initial induction of the ROS sensor AMP-activated protein kinase (AMPK) (Dando et al, 2013). More recently, CBD has been shown to enhance the ability of THC to inhibit tumor progression in mice bearing BRAF wildtype melanoma xenografts through activation of autophagy-mediated cell death (Armstrong et al, 2015). …”