Anticancer mechanisms of cannabinoids

Abstract

In addition to the well-known palliative effects of cannabinoids on some cancer-associated symptoms, a large body of evidence shows that these molecules can decrease tumour growth in animal models of cancer. They do so by modulating key cell signalling pathways involved in the control of cancer cell proliferation and survival. In addition, cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals. In this review, we discuss the current understanding of cannabinoids as antitumour agents, focusing on recent discoveries about their molecular mechanisms of action, including resistance mechanisms and opportunities for their use in combination therapy. Those observations have already contributed to the foundation for the development of the first clinical studies that will analyze the safety and potential clinical benefit of cannabinoids as anticancer agents.

Keywords: Cannabinoids; angiogenesis; apoptosis; autophagy; cell proliferation; cell signalling; combination therapy.

FIGURE 1

Cannabinoid-induced apoptosis relies on the stimulation of endoplasmic reticular (ER) stress and autophagy. Here, the mechanism of cannabinoid-induced apoptosis in glioma, pancreatic, and hepatocellular carcinoma cells is depicted. This signalling route could constitute the main mechanism of cannabinoid-induced cell death, with some variations inherent to different types of cancer cells. CB1 = cannabinoid CB1 receptor; CB2 = cannabinoid CB2 receptor; SPT = serine palmitoyltransferase; elF2α = eukaryotic translation initiation factor 2α; P inscribed in a circle = protein phosphorylation upon treatment with Δ⁹-tetrahydrocannabinol (THC); ATF-4 = activating transcription factor 4; CHOP = C/EBP homologous protein; AKT = protein kinase B; TRIB3 = tribbles-homologue 3; mTORC2 = mammalian target of rapamycin complex 2; CDKs = cyclin-dependent kinases; pRb = retinoblastoma protein; CaCMKKβ = calcium/calmodulin–dependent protein kinase kinase 2β; AMPK = AMP-activated protein kinase.

FIGURE 2

Possible strategies for optimizing cannabinoid-based therapies against gliomas. GF = growth factors; Abs = antibodies; MDK = growth factor midkine; VEGF = vascular endothelial growth factor; RTK = receptor tyrosine kinase; ALK = anaplastic lymphoma receptor tyrosine kinase; EGFR = epidermal growth factor receptor; CB1 = cannabinoid CB1 receptor; CB2 = cannabinoid CB2 receptor; AREG = amphiregulin; ER stress = endoplasmic reticular stress; ERK = extracellular signal-regulated kinase; TMZ = temozolomide; TRIB3 = tribbles-homologue 3; AKT = protein kinase B; mTORC1 = mammalian target of rapamycin complex 1.