The endocannabinoid system and cancer: therapeutic implication
Abstract
The endocannabinoid system is implicated in a variety of physiological and pathological conditions (inflammation, immunomodulation, analgesia, cancer and others). The main active ingredient of cannabis, Δ-tetrahydrocannabinol (Δ-THC), produces its effects through activation of CB1 and CB2 receptors. CB1 receptors are expressed at high levels in the central nervous system (CNS), whereas CB2 receptors are concentrated predominantly, although not exclusively, in cells of the immune system. Endocannabinoids are endogenous lipid-signalling molecules that are generated in the cell membrane from phospholipid precursors. The two best characterized endocannabinoids identified to date are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Here we review the relationship between the endocannabinoid system and anti-tumour actions (inhibition of cell proliferation and migration, induction of apoptosis, reduction of tumour growth) of the cannabinoids in different types of cancer. This review will focus on examining how activation of the endocannabinoid system impacts breast, prostate and bone cancers in both in vitro and in vivo systems. The therapeutic potential of cannabinoids for cancer, as identified in clinical trials, is also discussed. Identification of safe and effective treatments to manage and improve cancer therapy is critical to improve quality of life and reduce unnecessary suffering in cancer patients. In this regard, cannabis-like compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients. Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted.
LINKED ARTICLES
This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7
Human and murine* cell line/tissue.
↑, increase; ↓, decrease; –, not tested; 2-AG, 2-arachidonoyl glycerol; apo, apoptosis; AEA, anandamide; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; CBC, cannabichromene; CBD, cannabidiol; CBD acid; cannabidiol acid; CBG, cannabigerol; CBN, cannabinol; Δ-THC, delta 9-tetrahydrocannabinol; DALN, desacetyllevonantradol; FAAH, fatty-acid amide hydrolase; MET, methanandamide; mig, migration; no Δ, no change; NPD, N-palmitoyl dopamine; NPT, N-palmitoyl tyrosine; PEA, palmitoylethanolamide; pro, proliferation; siRNA, silencing RNA; SR1, SR141716A; SR2, SR144528; THC acid, tetrahydrocannabinol acid; WB, Western blot; WIN-2, WIN55,212-2.
↑, increase; ↓, decrease; –, not tested; ang, angiogenesis; apo, apoptosis; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; CBD, cannabidiol; Δ-THC, deltat 9-tetrahydrocannabinol; immuno, immunodeficient; i.p., intraperitoneal; MET, methanandamide; MMTV-neu mice, genetically engineered mice of ErbB2 (tyrosine kinase receptor)-driven metastatic breast cancer; NA, not applicable; no Δ, no change; pro, proliferation; p.t., peritumoral; PyMT mice, transgenic mice developing mammary gland tumours; s.c., subcutaneous; SCID-NOD, devoid of anti-tumour immune response; SR1, SR141716A; SR2, SR144528; WIN-2, WIN55,212-2.
↑, increase; ↓, decrease; –, not tested; 2-AG, 2-arachidonoyl glycerol; AEA, anandamide; apo, apoptosis; {"type":"entrez-protein","attrs":{"text":"CAY10401","term_id":"290784415","term_text":"CAY10401"}}CAY10401, fatty-acid amide hydrolase inhibitor; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; CBC, cannabichromene; CBD, cannabidiol; CBD acid, cannabidiol acid; CBG, cannabigerol; Δ-THC, delta-9 tetrahydrocannabinol; EPEA, eicospentaenoyl ethanolamide; FAAH, fatty-acid amide hydrolase; MAFP, methyl arachidonyl fluorophosphonate; MET, methanandamide; no Δ, no change; OTFP (3-octylthio-1,1,1-trifluoropropan-2-one; PEA, palmitoylethanolamide; pro, proliferation; SR1, SR141716A; SR2, SR144528; THC acid, tetrahydrocannabinol; WIN-2, WIN55,212-2.
↑, increase; ↓, decrease; –, not tested; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; DRG, dorsal root ganglion; FAAH, fatty-acid amide hydrolase; ipsi, ipsilateral side; no Δ, no change; NA, not applicable; WIN-2, WIN55,212-2.
↑, increase; ↓, decrease; –, not tested; AEA, anandamide; ACEA, arachidonyl-2′-chloroethylamide; BT, bar test; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; HP, hot plate; i.p., intraperitoneal; i.pl., intraplantar; i.t., intrathecal; LU, limb use; no Δ, no change; OF, open field; s.c., subcutaneous; SF, spontaneous flinches; SR1, SR141716A; SR2 SR144528; TF, tail flick; VF, von Frey; WIN-2, WIN55,212-2; WB, weight bearing.
Acknowledgments
Dedicated to my mother, Manon Marcotte, who passed away early 2011 of lymphoma (JG) and all the people who have lost their battles against cancer and to all those who are still fighting this dreadful disease. JG is supported by a Fonds de la recherche en santé du Québec (FRSQ) postdoctoral fellowship. AGH is supported by {"type":"entrez-nucleotide","attrs":{"text":"DA021644","term_id":"78408356","term_text":"DA021644"}}DA021644 and {"type":"entrez-nucleotide","attrs":{"text":"DA028200","term_id":"79204095","term_text":"DA028200"}}DA028200.
Glossary
Abbreviations
| 2-AG | 2-arachidonoylglycerol |
| AC | adenylyl cyclase |
| ACEA | arachidonyl-2′-chloroethylamide |
| AEA | anandamide |
| AKT | protein kinase B |
| AR | androgen receptor |
| ATP | adenosine triphosphate |
| Bax | pro-apoptotic protein |
| Bcl2 | anti-apoptotic protein |
| brca1 | breast cancer susceptibility gene product |
| cAMP | cyclic adenosine monophosphate |
| CBD | cannabidiol |
| CB | cannabinoid |
| CB1 | cannabinoid receptor 1 |
| CB2 | cannabinoid receptor 2 |
| CBN | cannabinol |
| Cdc2 | p34 cyclin-dependent kinase 1 |
| CDK | cyclin-dependent kinases |
| CNS | central nervous system |
| DALN | desacetyllevonantradol |
| Δ-THC | delta 9-tetrahydrocannabinol |
| DRG | dorsal root ganglion |
| EGF | epidermal growth factor receptor |
| EPEA | eicosapentaenoyl ethanolamide |
| ERK | extracellular regulated kinase |
| FAAH | fatty-acid amide hydrolase |
| GPR55 | G-protein-coupled receptor 55 |
| H2O2 | hydrogen peroxide |
| p27/KIP1 | cyclin kinase inhibitor |
| p38MAPK | p38 mitogen-activated protein kinase |
| PRL | prolactin receptor |
| MET | methanandamide |
| MGL | or MAGL, monoacylglycerol lipase |
| OTFP | 3-octylthio-1,1,1-trifluoropropan-2-one |
| p53 | p53 protein |
| p21ras | p21 ras protein |
| PEA | palmitoylethanolamide |
| PI3K | phosphatidyl inositol 3 kinase |
| PKA | protein kinase A |
| PKB | protein kinase B |
| PRL | prolactin receptor |
| PSA | prostate-specific antigen |
| Raf-1 | protein Raf-1 |
| RT-PCR | reverse transcriptase polymerase chain reaction |
| Trk | high-affinity nerve growth factor receptor |
| TRPV1 | transient receptor potential cation channel V1 |