Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

Abstract

Cannabinoids include the active constituents of Cannabis or are molecules that mimic the structure and/or function of these Cannabis-derived molecules. Cannabinoids produce many of their cellular and organ system effects by interacting with the well-characterized CB1 and CB2 receptors. However, it has become clear that not all effects of cannabinoid drugs are attributable to their interaction with CB1 and CB2 receptors. Evidence now demonstrates that cannabinoid agents produce effects by modulating activity of the entire array of cellular macromolecules targeted by other drug classes, including: other receptor types; ion channels; transporters; enzymes, and protein- and non-protein cellular structures. This review summarizes evidence for these interactions in the CNS and in cancer, and is organized according to the cellular targets involved. The CNS represents a well-studied area and cancer is emerging in terms of understanding mechanisms by which cannabinoids modulate their activity. Considering the CNS and cancer together allow identification of non-cannabinoid receptor targets that are shared and divergent in both systems. This comparative approach allows the identified targets to be compared and contrasted, suggesting potential new areas of investigation. It also provides insight into the diverse sources of efficacy employed by this interesting class of drugs. Obtaining a comprehensive understanding of the diverse mechanisms of cannabinoid action may lead to the design and development of therapeutic agents with greater efficacy and specificity for their cellular targets.

Function of the Endocannabinoid System in Neurodegenerative Diseases and Cancers

“…Furthermore, JWH-015, a CB2R agonist, inhibited Aβ-induced CD-40 mediated microglial phagocytosis [18]. In addition to targeting CBRs in AD, studies have shown WIN-55,212-2 preferentially targeting non-CBRs in colon, colorectal, and prostate cancer and therapeutically functioned to reduce tumor growth and proliferation [19] [20] [21]. Other studies investigating non-CBR targets in various cancers such as glioma, myeloma, and lung; the drugs cannabidiol, cannabigerol, and methanandamide worked as agonists to induce apoptosis [22]- [28].…”

“…In vitro and in vivo studies provide evidence that suggests efficacy of cannabinoid agonists in reducing tumor growth and proliferation [19]. Δ 9 -THC has been used as an approved treatment for cancer patients with AIDS experiencing chemotherapy-induced nausea, vomiting, and anorexia [78].…”

“…Moreover, Δ 9 -THC was identified as potent RAS-MAPK and PI3K-AKT signaling inhibitor inducing BAD-mediated apoptosis in CRC cells; findings indicate that CB1R and proapoptotic BCL-2 family member BAD play a role in regulating the apoptosis in CRC cells [80]. In addition to receptor targets, other cancer-related off-receptor targets have been identified to mediate their effects on cancer by interacting with the endocannabinoid systems and its various components and cannabinoid ligands [19]. Although other cancers-such as lung cancer, colon cancer, and pancreatic cancer-have been identified to interact with the endocannabinoid system, additional mechanistic studies are warranted to further investigate CBR's regulatory functions [5]…”

Effect of endocannabinoid signalling on cell fate: life, death, differentiation and proliferation of brain cells

“…Recently, a novel series of AEA-derived prostamides, prostamides J, have been demonstrated to induce apoptosis in a receptor-independent way (Soliman and Van Dross, 2016). Some of the effects previously mentioned to be responsible for the apoptosis induced by AEA, such as ER stress, oxidative stress and action on lipid raft microdomains, have now been reported to be receptor-independent (Soderstrom et al, 2017).…”

Cannabinoid interactions with ion channels and receptors

“…Although prevalent thought held that cannabinoids bind exclusively to CB1 and CB2, this has been proven to be false by countless studies showing interactions between cannabinoids and other membrane proteins [13][14][15][16][17][18]. Whereas some cannabinoids still interact with CB1 and CB2, they also interact with a large range of targets including other receptors, transporters, enzymes, cellular structures, membranes, and ion channels [19,20]. The intent of this review is to focus on the last two listed targets; cellular membranes and ion channels.…”