12.5.6 Signaling Pathways Associated With Cannabinoid Receptor

Activation (Fig. 12.3)

12.5.7 Clinical Trials

Preclinical models proposed the anticancer role of cannabinoids, notably by

inhibiting cell proliferation, angiogenesis, metastasis, and invasiveness. Several

cell signaling pathways that are involved in the antitumor activity of cannabinoids

implicated the connection between ESC system and cancer. There are eight ongoing/

completed clinical trials representing the antitumor effect of cannabinoids in various

cancer types. Apart from their antitumor activities, these trials also aimed to assess

Fig. 12.3 Schematic representation of cannabinoid receptor-mediated downstream signaling cas-

cade in various cancers: (i) non-cannabinoid receptors after interaction with cannabinoid ligands

activate the JAK/STAT pathway. (ii) Apoptosis is induced by activation of CB1 receptor and

increase in the ratio of Bax/bcl-2 occurs, which in response upregulates the expression of PARP and

caspases 3 and 9. (iii) CB1 receptors act through Gi/o protein and activate ERK1/2 which in

response activate p27/kip1 protein and bring induced cell cycle arrest via inactivation of cyclins.

(iv) CB1 and CB2 receptors interact with Gi/o protein which inhibits adenylyl cyclase and

subsequently

elicits

the

cAMP

accumulation,

which

ultimately

leads

to

apoptosis.

(v) Downregulation of MMP-2, MMP-7, MMP-9, and VEGF-A leads to inhibition of angiogenesis,

metastasis, and invasion of cells. (vi) CB2 receptors stimulate the release of ceramide (second

messenger) which inhibits AKT signaling following mTOR pathway causing programmed cell

death. (vii) Additionally, proapoptotic protein TRB3 is activated which in response induces ER

stress in a cell and ultimately causes apoptosis. (viii) CB2 receptor also leads to inhibition of

FAK-src pathway which eventually induces apoptosis. (ix) Apart from cannabinoid receptors,

non-CB receptors are involved in cell lysis via activation of lymphokine-activated killer

12

Emerging Role of Cannabinoid System Modulators in Treatment of Cancer

193