inactivation, ceramide, a proapoptotic lipid, acts as a second messenger for

cannabinoids. Thus, JWH015 (CB2 agonist) induces cell apoptosis through the

stimulation of de novo synthesis of ceramide and inhibits the pro-survival signal

Akt. This study has also suggested the impact of CB2 receptor activation in bladder

cancer cell migration and aggressiveness via the inactivation of the FAK-Src path-

way (Bettiga et al. 2017). Hence, this finding establishes the role of cannabinoid as

anti-metastatic and antiproliferative agent.

12.5.5.3 Pancreatic Cancer

Pancreatic cancer is one of the leading causes of cancer death and is categorized

among the most aggressive cancer. The use of cannabinoids was earlier restricted to

palliative care for cancer patients. Thus, researchers started exploring anticancer

effects of cannabinoids in various cancer types. Cannabinoid receptors are found to

be upregulated in pancreatic cancer. Studies showed that that activation of CB2

receptors and inactivation of CB1 receptors may induce cell apoptosis. MiaPaCa-

2 (pancreatic cancer cell line) manifested substantial cell death after treatment with

CB receptor synthetic agonist (WIN-55,212-2 and JWH-015) (Fogli et al. 2006).

Additionally, it has been demonstrated in a study that the inverse agonist of CB1

receptor (AM251) induced apoptosis in MiaPaCa2 cells and also affected transcrip-

tional genes via the JAK/STAT and MAPK signaling (through CB1 receptor-

independent pathways) (Fogli et al. 2006).

The study by Michalski et al. revealed the inverse correlation between CB1

receptor and patient survival. During this investigation, the cannabinoid receptors

were evaluated along with the endocannabinoid metabolizing enzymes; fatty acid

amide hydrolase (FAAH) and monoacylglycerol lipase (MGLL) in both normal and

pancreatic cancer cell from patients. This study showed the correlation between high

FAAH/MGLL levels and survival of cancer patient (Michalski et al. 2008).

Additional studies on other pancreatic cancer cell line Panc1 cells supported the

evidence of cannabinoids as antitumor agents. Treatment of cells with CB2 agonist,

GW405,833 hydrochloride (GW), has been demonstrated to inhibit the proliferation

and invasion. GW activates AMPK and autophagy in pancreatic adenocarcinoma

cells by increasing AMP/ATP ratio. Autophagy induction evaluated to be related to

inhibition of energy metabolism which is dependent on ROS production (Dando

et al. 2013). Treatment of Panc1 cells with THC led to caspase 3 activation. This

study explored the role of THC on the xenografted MiaPaca2 pancreatic mice model.

Inhibitory effect of cannabinoids was established in the pancreatic tumor growth

post-treatment. Cannabinoid agonist WIN 55-212,2 also decreases the cell growth in

pancreatic cancer cells through possibly the activation of TRB3, a proapoptotic

protein (downstream protein of p8 and ATF-4) responsible for the apoptosis induced

by ER stress (Carracedo et al. 2006). Thus, induction of apoptosis by CB2 agonist is

hypothesized to slow the progression of pancreatic cancer in patients.

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