June 2012
Daniel J. Hermanson and Lawrence J. Marnett
Introduction
Cannabinoid Function
Endocannabinoids are bioactive lipids that have a range of interesting activities mediated by two G-protein-coupled receptors (CB1 and CB2) and other putative targets [1-3]. The CB1 receptor is present in the central nervous system and mediates the psychotropic effects of exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC), the active component of marijuana.
In the brain, endocannabinoids and cannabinoids combine with CB1 cannabinoid receptors on axon terminals and regulate ion channel activity and neurotransmitter release [4].
Binding to the CB1 receptor is responsible for the analgesic activity of endocannabinoids as well as many other effects including locomotion and temperature control [5]. The CB2 receptor is present in inflammatory tissues and mediates the anti-inflammatory effects of endocannabinoids and plant-derived cannabinols [6]. Both the CB1 and CB2 receptors couple to Gi and reduce intracellular cAMP levels.
Conclusions
Cannabinoids exert a number of interesting effects that are dependent on the cell line or tumor type. Synthetic cannabinoids and the endocannabinoid system are implicated in inhibiting cancer cell proliferation and angiogenesis, reducing tumor growth and metastases, and inducing apoptosis. Some studies suggest that abnormal regulation of the endocannabinoid system may promote cancer by fostering physiological conditions that allow cancer cells to proliferate and migrate.
For this reason, the endocannabinoid is an attractive target for pharmacological intervention in the treatment of cancer. Modulation of the endocannabinoid system to treat cancer may provide a targeted treatment of cancer, which has been shown in several studies that demonstrated selective action of cannabinoids on tumor cells while not having effects on normal cells.
The endocannabinoid system is involved in a complex set of signaling pathways including activity at the CB1, CB2, TRPV1, and GPR55 receptors, and through receptor-independent actions. The complexity of the signaling pathways involved in endocannabinoid action both in normal and malignant tissues offer a significant research obstacle, however, several important pathways have been elucidated.
These include modulation of pathways critical to cell proliferation, cell cycle, and apoptosis. The diversity of receptors and signaling pathways that the endocannabinoid system modulates offers an interesting opportunity for the development of specific molecules to perturb the system selectively, as has already been achieved in the development of agonist and antagonists of the CB1, CB2, TRPV1, and GPR55 receptors.
In addition, recent work has revealed that COX-2, which is involved in the progression of several types of cancer, modulates endocannabinoid tone at sites of inflammation [135]. The oxygenation of endocannabinoids by COX-2 or other enzymes may also play a critical role in the influence of endocannabinoids on cancer.
Although there is a strong set of data in vitro, in cellular model systems, and in mouse model systems, there is a dearth of clinical data on the effects of cannabinoids in the treatment of cancer in humans.
This fact is quite surprising considering the large library of compounds that have been developed and used to study the effects of cannabinoids on cancer in model systems. Despite the lack of preclinical and clinical data, there is a strong agreement that pharmacological targeting of the endocannabinoid system is emerging as one of the most promising new methods for reducing the progression of cancer.
In particular, combination therapy utilizing both traditional chemotherapeutics and molecules targeting the endocannabinoid system may be an excellent next generation treatment for cancer.
