Endocannabinoid Cancer Inhibition Pathway

The endocannabinoid system comprises two GPCR receptors, CNR1 and CNR2, their endogenous ligands, the endocannabinoids, and the enzymes that regulate endocannabinoid biosynthesis, degradation, and tissue levels. CNR1 receptors are expressed at high levels in the central nervous system, whereas CNR2 receptors are concentrated predominantly, although not exclusively, in cells of the immune system.Endocannabinoids are endogenous lipid-signaling molecules that are generated in the cell membrane from phospholipid precursors. The two best characterized endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). AEA is an unsaturated fatty acid derivative belonging to the N-acylethanolamide group and it is hydrolyzed to arachidonic acid and ethanolamine by an intracellular fatty acid amide hydrolase (FAAH). 2-AG is hydrolyzed mainly by monoacylglycerol lipase (MAGL).The endocannabinoids and natural or synthetic cannabinoids inhibit cancer cell proliferation, arrest the cell cycle, induce cell death, mainly through apoptosis and autophagy, prevent tumor spread (metastasis formation), and inhibit oxygen and nutrient supply by blocking angiogenesis in the tumor environment. Growth inhibitory activities have been demonstrated both in vitro and in vivo for various malignancies, including brain, breast, prostate, colorectal, skin, thyroid, uterine cervix, pancreatic cancer, leukemia, and lymphoid tumors. Endocannabinoids induce de novo synthesis of ceramides which lead to activation of ERK-signaling cascade to promote apoptosis and prevent cell proliferation in various types of cancer cells, including those associated with glioma, leukemia, colon, and pancreatic cancer. The increase in ceramide can also activate the p38 mitogen-activated protein kinase pathway which can lead to apoptosis through activation of cysteine proteases (i.e. caspases). Inhibition of the Akt-mTORC1 pathway or activation of AMP-activated kinase (AMPK) could also be responsible for induction of autophagy. The inhibitory effect on migration and invasion through CNR1 and CNR2 is related to blocking of key pathways such as FAK-Src-RhoA and of matrix metalloproteinases. Inactivation of the PI3K/Akt pathway leads to lower HIF-1 and VEGF levels, which are known as proangiogenic molecules.On the other hand, cannabinoids can repress immune system functions, which can compromise their many other anti-cancer effects.