12.5.5 Evidences Supporting Cannabinoid System Modulators

as Effective Anticancer Agents (In Vitro and In Vivo Studies)

12.5.5.1 Prostate Cancer

Prostate cancer is one of the most common malignancies in men and also the second

leading cause of cancer-related death. Various studies had been conducted focusing

on the role of cannabinoid receptors in prostate cancer in vitro. Effect of WIN

55,212-2 has been described in various studies of prostate cancer. WIN 55,212-

2 causes cell mortality, decreases the expression of proapoptotic protein, and

upregulates anti-apoptotic. LNCaP (prostate cancer) cell line has high expression

of CB1 and CB2 receptors, when subjected to WIN 55,212-2 resulting in a decrease

of cell viability. Decrease in the expression of Bcl-2 protein has also been observed

after the treatment with this agonist. Additionally, 24 hours post-treatment

upregulation of Bax protein expression has been found in these cells. Therefore,

the ratio of Bax to Bcl-2 sighted in this study deduced that apoptosis has been

favored by the activation of caspase 9 and 3 with concomitant cleavage of PARP

(poly ADP-ribose polymerase). This study also indicates that cannabinoid receptor

agonist (WIN 55,212-2) induces activation of ERK1/2, which leads to induction of

cyclin kinase inhibitor p27/KIP1. Sequentially, it inhibits the cell cycle regulatory

molecules (cyclin D1, D2, E) and results in cell cycle arrest at G1 phase and causes

apoptosis (Sarfaraz et al. 2006).

The effect of WIN 55,212-2 is also demonstrated in an in vivo investigation by

Roberto et al. on PC3 xenograft model. Results in this study revealed that intraperi-

toneal administration of WIN 55,212-2 thrice weekly over a 3-week period signifi-

cantly reduces the tumor growth rate and no significant associated toxicities were

found (Roberto et al. 2019).

In another study, the androgen-sensitive prostate cancer cell CWR22R ν1 xeno-

graft model has demonstrated the similar results where the intraperitoneal adminis-

tration of WIN 55,212-2 significantly suppressed the tumor growth along with

reduction in PSA secretions in the serum (Sarfaraz et al. 2007).

All these studies delineate the role of WIN 55,212-2 as an anticancer agent which

hinders the growth, migration, and invasion of prostate cancer cells, in addition to

cell cycle arrest in G0/G1 phase and triggered apoptosis pathways.

12.5.5.2 Bladder Cancer

Bladder cancer is the ninth most common cancer in the world. Approximately 90%

tumors in urinary bladder are of epithelial origin. Bladder carcinomas comprise of

two different categories: (a) superficial non-muscle invasive papillary lesions, which

are indolent lesion, and (b) muscle invasive bladder cancer (MIBC), which is an

aggressive cancer with much poorer prognosis. Available literature on bladder

cancer study supported the specific use of CB2 receptors as antitumor targets.

Activation of CB2 receptor has been demonstrated to produce anticancer effect by

inactivation of two mechanisms mTORC1 and FAK-Src pathways. During mTOR

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