Use Of Cannabinoids in Cancer Treatment

 

Summary

The medicinal and therapeutic properties of cannabinoids have facilitated their application in various disease treatments for an extended. The activity of cannabinoids is regulated by endocannabinoid system (ECS), which comprises of cannabinoid transporters, enzymes for synthesis and breakdown and receptors. In the modern world, cannabinoids are gaining popularity due to their associated ability to stop cancer cell proliferation and human death (Salazar2009).

However, the anti-cancer effects of cannabinoids have been investigated mainly through in vitro models which may be insufficient in imitating tumor growth and metastasis (Donadelli et. al 2011)Thus, this article reviews some of the studies that investigated the effects of cannabinoids either synthetic, endogenous or their extracts in cancer development. Moreover, it examines the treatment in clinical, in vitro and in vivo models to explore the current efficiency in the cannabinoids being used in the treatment of patients tested for cancer.

Cannabinoids are products of two types of plants; drug plants and hemp plants. More focus is attached to drug plants which comprise of THC and CBD due to their role in cancer treatment and precisely their role in pancreatic cancer. Cannabidiol (CBD) refers to a compound containing desirable medical characteristics and does not result in stoning effect (Borgelt et al. 2013). THC (Tetrahydrocannabinol) refers to the chemical responsible for most psychological effects attributed to marijuana (Martin 2016). In addition to reviewing previous studies, this article aims at evaluating; the cannabinoids receptors and their role in cancer therapy, cannabinoids mechanisms of action, cannabis effects on immune cells, effects of cannabis on inflammation and fibrosis in pancreatic stellate cells, the advantages and disadvantages of THC and CBD, and Roles of Cannabis in pancreatic cancer (Alina 2017).

 

THC and CBD Plants

There are two types of plants from which cannabis is extracted. These are categorized into hemp plants and drug plants. Hemp plants are grown for fiber and seed oil production. On the other hand, drug plants are THC and non-euphoric CBD-rich plants (Martin 2016).The content of resin acts as the main difference between the two plants. Hemps plants are known to contain low resin levels while drug plants are high in resin levels (Martin 2016).

Agricultural hemp crops grown for industrial purposes are usually those with low resin levels. These crops are mothered from pedigree seeds usually a hundred tall, skinny plants planted a square meters apart. These plants are harvested mechanically and manufactured into several products (Martin 2016). On the contrary, drug plants for industrial purposes are horticultural crops with high resin levels and are produced by asexually reproduced clones, planted 1 to 2 plants a square meters apart. Moreover, they are hand harvested, dried, trimmed and cured (Martin 2016).

Definitions

Cannabidiol (CBD) refers to a compound that contains desirable medical characteristics and does not result in stoning effect. However, it can act against THC psychoactivity.  Cannabis which is rich in CBD is less psychoactive than THC. However, its dominant strains make it more suitable in relieving spasms, pain, psychosis, anxiety, and inflammation, among other conditions with no effects on lethargy or dysphoria feelings (Borgelt et al. 2013).

THC (Tetrahydrocannabinol) refers to the chemical responsible for most psychological effects attributed to marijuana. It functions like any cannabinoid chemical that the body produces naturally.  Cannabinoid receptors are contained at high concentrations in specific brain regions which are associated with an individual’s feelings, thinking, perception, memory, and coordination. THC binds to these receptors, activates them and affects their activities (Alina 2017).

CB1 and CB2 Receptors

Over the recent years, interest in cannabinoids is increasing because of their potential against neoplastic, cachectic, and analgesic. These synthetic cannabinoids assume the activities of their original counterparts’, i.e., arachidonoylglycerol (AG) and anandamide (AEA). Just like their endogenous duplicates, they activate specific receptors(Carlisle et.al 2002)These receptors include cannabinoid receptor-1(CBD) 6 which is found in neural tissues in large numbers and Cannabinoid receptor-2 (CB2)7 which is specifically found on the immune system cells and are members of G-Protein family (Marsicano et.al 2003)

Despite the fact that cannabinoids have demonstrated the ability to induce death of cancer cells, they have also been associated with inhibition of tumor vascularisation. They do so by altering the morphology of blood vessels and reducing blood vessels proangiogenic factors including VEGF. Additionally, they are known for their ability to reduce cancer cells proliferation (van et.al 2005). There is a correlation between low CBI receptors and more prolonged survival for patients with pancreatic cancer. Moreover, cannabinoid receptors, i.e., CB1 and CB2 can induce pain development in pancreatic patients (Michalski 2008).

A study by (Preet et al. 2011) on Non-Small Cell Lung Cancer (NSCLC) showed that expression of CB2 receptor was high than the expression of CB1 receptors in patients with NSCLC.  Treatment of NSCLC with CB1/CB2 was found to increase the growth factor-directly in vitrochemotaxis and chemoinvasion in cells. Also, pretreatment with the two cannabinoid receptors was found to increase inhibition of in vitro chemotaxis and chemoinvasion (Ben et.al 2003). Additionally, they inhibited the growth of in a vitro tumor and lung metastasis.  Moreover, the agonist CB 1 and 2 inhibited AKT phosphorylation a molecule that signals control of apoptosis, migration survival and decreased MMP-9 expression and activity (Salazanet et.al 2007). Therefore, CB1 and CB2 can be used therapeutically to fight against NSCLC.

Mechanism of Action

A decade of years ago, the ability and properties of cannabis compounds against cell proliferation were discovered. The first discovery was linked to D-THC ability to inhibit the growth of lung adenocarcinoma cells in vitro and in vivo. The invention of anti-tumor properties of cannabinoids happened two decades later (safaraza et.al 2008). To this end, in vitro models for different cancer types have been deployed to elucidate mechanisms by which these cannabinoid and endocannabinoids influences the migration, proliferation, and apoptosis of cancer cells. However, the mechanisms of action to control cancer cell proliferation, migration and apoptosis of these cannabinoids/endocannabinoids are complex leaving a gap in understanding of the complete process. Additionally, these mechanisms are different in each type of cancer; hence, the pro and anti-apoptotic effects of cannabinoids are reported (Laezza et.al 2006).

Some mechanisms can indicate the proapoptotic cannabinoids effects and explain their ability to fight cancer. Cannabinoids stimulate the production ceramides (Ligresti et.al 2006). This occurs by activation of ceramide synthase enzyme which causes a downstream activation of the cascade that signals Extracellular Regulated Kinase (ERK). This leads to cell cycle arrest and apoptosis. When CB1 and CB2 receptors are activated, the ceramide-ERK signaling pathway is triggered by the promotion of apoptosis. An increase in ceramide can also lead to p38 mitogen-activated protein kinase (p38MAPK) pathway activation. This can result in apoptosis through several mechanisms (Del Pulgar 2000).

CB1 or CB2 receptors activation inhibits the activity of adenylyl cyclase (AC) and decreases the levels of cyclic adenosine monophosphate (cAMP) and operation of Protein Kinase A (PKA).  As a result, there is a decrease in gene transcription regulation resulting in apoptosis. Moreover, apoptosis can occur when transient receptor potential channels V1 (TRPV1) are activated. This increases the intracellular levels of hydrogen peroxide and calcium or mitochondria production of cytochrome C leading to apoptosis by distinct and overlapping mechanisms (lauezza et.al 2008).

The pro-apoptotic properties of cannabinoid receptor one are seen through its ability to inhibit Ras protein (p21 ras) that is part of DNA synthesis (Bifulco et al., 2001).  However, activation of cannabinoid receptor one can similarly induce activation of different types of tumor cascades which are associated with promoting cancer cells survival and inhibiting apoptosis. CB1 ligands activate P13K/PKB which is a crucial tumor pathway implicating cell survival (Sanchez 2003). However, P13K/PKB activation by CB1 activation can lead to apoptosis directly or by p27/K1P1inhibition. This raises the probability that deregulation of endocannabinoid system can also cause anticancer effects by inhibiting migration of cancer cells (Blazquez et al., 2003; Kogan, 2005). It is, therefore, necessary to conduct more research to discover the stability of these mechanisms and how they influence cancer in vivo (Guindon 2011).

 

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Effects of Cannabis on the Immune Cells in Cancer

Cannabinoids from cannabis plant have immunosuppression effects whose mechanism of action has been investigated in vivo and vitro researches. These studies have depicted the impact of cannabis product on different immune cells (Chen and Buck 2000). Cannabinoids’ exert their activities on the immune cells by inhibiting the adenylate cyclase activity leading to blockage of forskolin-stimulated Camp activation. Thus there is a decrease in protein kinase A action, and subsequent reduction of transcription binding to CRE sequence. As a result, IL-2 production is destructed leading to reduced production of IL-2 cells (Chen and Buck 2000).Other studies have shown that treatment of NK cells with THC causes alterations in the IL-2 receptor, thus, decreasing the binding sites for IL-2 and subsequently makes the IL-2 stimulated cells unable to destroy EL-4 cyst cell (Zhu et al. 1995).

In several studies, cannabis smoking has proven to suppress the functions of the immune system, thereby increasing the chances of infections (Tashkin et al. 2002).  In vitro, studies show that THC affects the immune cells directly by blocking lymphocytes proliferation. According to (Anandamide 1994) some cannabinoid receptors induce apoptosis of lymphocytes in humans. Moreover, THC was also seen to induce apoptosis in murine macrophages and T cells through regulation of Bc1-2 caspase activity (Zhu et al. 1998). In vivo tests, THC was demonstrated to reduce the spleen and thymus cellularity which affected several types of cells including macrophages, T cells and B cells.

Effects of Cannabis on Inflammation and Fibrosis in Pancreatic Stellate Cells

The ability of cannabinoids to modulate the immune system and their ability to influence lymphocyte makes them suitable for treatment of many inflammatory diseases.  Additionally, they have recently been reported to affect liver fibrogenesis by application of several mechanisms (Sanchez et.al 2005). Several studies have been conducted to determine the role of cannabinoids on liver fibrogenesis. Endocannabinoid anandamide has been demonstrated experimentally to stimulate necrosis in hepatic stellate cells which are CB1 and CB2 receptors independent. However, CB2 receptor activation on hepatic stellate cells has been shown to cause apoptosis and liver fibrosis in induced liver cirrhosis (Sanchez et.al 2005).  To this end, antagonism of CB1 has been proposed to be the new approach for liver fibrosis treatment. All these together serve to help reduce or eliminate liver fibrogenesis. Activation of cannabinoid receptors stimulates a dormant phenotype chronic PSC derived from pancreatitis. This is done through reducing the production of extracellular proteins of the matrix and inflammatory cytokines (Akhmestshing et.al 2011). This is followed by a change in the appearance of the PSC into a reduced mesenchyme-like phenotype. PSC motility is therefore attributed to the invasive potential of PSC since its migration to damaged sites induces redifferentiation and tissue repair or can promote activation and fibrosis. Moreover, it has been observed that suppressing the invasiveness of PSC by activation of CB receptors is followed by a reduction in MMP-2 levels (Panch et.al 2011).This is essential in regards to invasiveness as well as the influence of altered matrix balance synthesis and degradation. This is based on the fact that increased MMP-2 levels enable deposition of pathogenic fibrillar collagens. Besides, it has been proposed that both hepatic stellate and pancreatic cells MMP-2 may affect their proliferation. Therefore, suppression of MMp-2 by cannabinoid inducement could help induce a dormant phenotype reducing collagen synthesis (Michalski et al. 2008).

Effects of CBD and THC on Different Type of Cancers

Cannabis sativa has been linked to several pharmacological benefits which can be attributed to two of its active compounds, CBD and THC. Although cannabinoids have been clinically applied as painkillers, current studies suggest that they could be used in the fight against cancer. This is because they possess both antiproliferative and anti-angiogenic properties in both vivo and vitro cancer tests.

THC, CBD on Pancreatic Cancer.

Pancreatic cancers of adenocarcinomas are among the most common types of cancer and thus, the need to set new approaches to diagnose and treat this life-threatening disease. Several studies have been conducted to investigate cannabinoid (CBD) effects on this type of cancer. A study by (Carracedo et al. 2006, Michalski et al. 2008) showed that expression of CB1 and CB2  is high in pancreatic cancer cell than it is in normal tissues of the pancreas (Martínez et al. 2015).Other studies were done using Miapaca2, and Panc1 cell lines illustrate the effects of cannabinoid administration (Ruberg et al. 2007.. Fernandez2007). In these studies, cannabinoid administration was found to increase ceramide levels, induce apoptosis, and Increase regulatory responses of mRNA levels of the stress protein p8. It was also found that blockade of CB2 cannabinoid receptor prevented the effects of cannabinoid administration. Similarly, pharmacological inhibition of ceramide de novo was observed to inhibit these effects (Mackie 2008).CBD was also found to reduce tumor cells growth in double animal models of a pancreatic tumor (Lient et al. 2004). Similarly, treatment with CBD was found to prevent the spreading of pancreatic tumor cells (Edward et al. 2005). Also, administration of cannabinoids demonstrated its ability to increase apoptosis expression of TRB3 selectively in pancreatic cancer cells and not healthy pancreatic cells (Rasmos 2006). Therefore, this depicts that cannabinoids cause pancreatic tumor cells to undergo apoptosis through CB2 receptor and up-regulation in p8 and stress-related genes. Under this study, the cannabinoid receptors expression was examined for both human tumor line and human pancreatic tumors biopsies. The results showed that CB2 receptor activation-induced apoptosis of pancreatic tumor cells in vitro (Rasmos 2006). Additionally, incubation of mRNA with THC led to a similar increase in mRNA, TRB3, p8 and ATF levels. However, incubation with ISP-1 blocked the effects. Additionally, inhibition of p8 mRNA was found to increase the regulation of TRB3 and avert ATF-4. Similarly, repression of three genes prevented apoptosis induced by THC. Altogether, these results demonstrate that THC stimulates apoptotic responses which are controlled by ceramide and p8 in pancreatic cancer cells. Another test was conducted to examine   CBD antiproliferative in vivo (Siegel et al. 2016).  It was noted that JWH-133 decreased the development of existing pancreatic neoplasms. Tests were also done using WIN55, 212-2 which are known for their excellent bioavailability. These test confirmed that this compound induced pancreatic cancer cell apoptosis through similar proapoptotic pathway as THC (Howled et al. 2002). Administration of this compound efficiently reduced intrapancreatic tumor growth as well as decreasing extending tumor cells. This indicates that cannabinoids treatment affects both the growth and spread of pancreatic cancer cells. Other tests also contributed to the conclusion that administration of cannabinoid produces apoptosis in pancreatic cells in vivo selectively (Carracedo et al. 2006).

CBD, THC and Brain Cancer

Brain cancer is one of the health hazards which continue to pose a threat to human life. Different cancers of the central nervous system such as the glial and neuronal cancers have been diagnosed in different individuals. These types of cancer are of different types and are mainly formed in the human mind (Siegel et al. 2016). As such, several therapeutic strategies should be implemented to help in the eradication of this deadly disease. Due to the increased demand for novel anti-cancer strategies researches have been made to examine the endocannabinoid system (ECS). These researches were conducted using humans and rodents in both preclinical and clinical models. From the studies it was noted that the functional components of ECS were able to express in both rodents and humans glioma tissues (Sánchez et al., 2001; Moreno et al., 2014).  However, it was notable that CB2 was highly expressed in high grade glioma tissues (Ellert-Miklaszewska et al., 2007).  Due to the therapeutic association of cannabinoids and cancer, evaluations have been made to verify the therapeutic effects of cannabinoids against glioma tumor. This aims at assessing the ability to develop these agents as therapeutic options against neoplastic (Jenkins et al., 2006).

Other studies have investigated the ability of THC to destroy glioma tissues. From the studies it was found that THC highly induced glioma cell death in vivo studies. Moreover, THC was found to reduce tumor growth through activation of Erk and ceramide synthesis (GalveRoperh et al., 2000).

CBD has been demonstrated to effectively reduce the growth of U87MG xenograft as compared with vehicle control (Massi et al., 2004). The anti-tumor effects have been attributed to the introduction of reactive oxygen species and subsequent activation of CB2 receptors.  Contrary to 19-THC, CBD the toxicity is not controlled by CB1 or ceramide.

Liver Cancer

Hepatocellular carcinoma (HCC) and Cholangiocarcinoma are the two major types of liver cancer that exist today. (Huang et al., 2011a). A study by Xu et al. found that cannabinoid receptors; CB1 and CB2 expressed continually in HCC tissue due to reduction in disease causing agents and prevention of their survival (Xu et al., 2006). Additionally, the study found that 19-THC could reduce the growth of HepG2 and HuH-7-derived tumor cells. They were also found to diminish the development of ascites in orthotropic HCC model. These antitumor effects were linked to activation of CB2 receptors and increase in ceramide, Er-stress, PPAR activity and autophagy induction respectively (Vara et al., 2011, 2013). Additionally, the growth of endocannabinoid, AEA, Mz-ChA-1 which had been derived from cholangiocarcinoma xenografts was reduced and subsequently resulted in a reduced regulation of tumor expression angiogenic factor (DeMorrow et al., 2008; Huang et al., 2011b).

Prostate Cancer

Prostate cancer refers to the proliferation of cancer cells in the male reproductive system specifically the prostate gland. This type of cancer is the most common cancer in men contributing to cancer-related deaths in men which can be linked to its late detections (Siegel et al. 2016). Nevertheless, Cannabinoids and cannabinoid receptors have demonstrated therapeutic benefits in the fight against this deadly disease. In another study, it was reported that there was an elevated expression of cannabinoid receptors in prostate cancer than in normal prostate tissues (De et al. 2013). Despite the fact that many studies have investigated the cannabinoids effects on prostate cancer in different studies, Reports in vivo models are limited. One of the studies showed that cannabis extract rich in CBD was effective in reducing cancer development in positive androgen receptors. However, it was found that the extract had the potential to promote tumor growth in negative androgen receptors (De et al., 2013). Additionally, in vitro tests showed that CBD reduced the expression of androgen receptors. CBD was also found to increase the generation of reactive oxygen species pro-apoptotic expression in prostate cancer lines. These antiproliferative effects were facilitated by ceramide synthesis by CB2 activity and were observed in in vitro (Siegel et al. 2016).

Skin cancer

Skin epidermis constitutes differing types of cells that include keratinocytes and melanocytes. These cell types are sources of nonmelanoma and melanoma skin cancers. Different in vivo studies have reported the anti-tumor effects of phyto and synthetic cannabinoids in the treatment of melanoma. 19-THC was found to reduce proliferation, increase death of tumor cells and reduce the growth of CHL-1 melanoma xenografts (Armstrong et al., 2015). According to (Glodde et al., 2015) the 19-THC anti-tumor effect was cannabinoid receptors independent.  By use of synthetic cannabinoid receptors deficient mice, the group showed that cannabinoid that constituted differing affinities for their receptors had made a way to target CB1 and CB2 receptors in melanoma potentially. Further analysis showed that mixing cannabinoid receptors agonist, WIN-55212, 2 reduced the growth and metastasis of B16F10 melanoma cells in mice (Naeem et al., 2006).  The anti-tumor effects of CB2 selective cannabinoids and JWH-133 were examined which showed that JWH-133 was similarly effective as WIN5212-2 in preventing the growth of a melanoma tumor. This suggested that CB2 receptor activation facilitated the antitumor activities of cannabinoid (Naeem et al., 2006).

Thyroid Cancer

Globally, the rates of thyroid cancer are relatively low in comparison to other existing cancer types. However, therapeutic strategies should be invented and implemented to aid in disease detection at early stages and prevent death resulting from this life-threatening disease (Shi et al. 2008).

Due to the positive association of cannabinoids with cancer, several studies have been conducted to evaluate the effects of cannabinoids on thyroid cancer. However, the existing in vivo reports of the same is limited. Nevertheless, these reports have demonstrated that the endocannabinoid system can control tumor growth through its expression (Bifulco et al. 2001). From the above study, it is evident that ECS manipulation is a feasible option for prevention of thyroid cancer. Further preclinical investigations were conducted by F-AEA. From these studies, it was discovered that met-F-AEF inhibited the growth of a thyroid tumor and the effect was revisable by CB1 receptor antagonism (Shi et al. 2008). Further, transfer of 1L-12 genes into thyroid carcinoma cell line was found to have anti-tumorigenic properties. These effects were attributed to the activation of the cannabinoid receptors.  The transfer of IL-12 gene into anaplastic thyroid carcinoma cell line (ARO) result in anti-tumorigenic effect. This effect resulted from the activation of the cannabinoid receptor. Additionally, CB2 agonist JWH-133 and cannabinoid receptors agonist WIN-55,212-2 were found to be apoptosis inducers in anaplastic thyroid and 1L-12 cells (Shi et al. 2008).

Lung Cancer

Lung cancer is of two major types; non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Risk factors for this disease include; genetic exposure, tobacco smoking, and radon gas exposure. Survival rates for this disease are low and demand a need for novel intervention. Thus, the effectiveness of cannabinoids in lung cancer treatment has been evaluated in vivo. The expression of CB 1 receptors in NSCLC was found to be low compared to that of CB2 in NSCLC. This suggested that CB receptors can play a role in tumor development (Preet et al., 2011). THC and CBD demonstrated differing effects in animal models for lung cancer. CBD when administered to mice with A549 cell xenografts was observed to decrease invasion, metastasis and tumor growth (Ramer et al., 2010a, b, 2012). A study on the THC by Preet et al. reported that 19-THC reduced the regulation of Akt in A549-derived xenografts that consequently lead to decreased tumor growth and metastasis (Preet et al., 2008).

Colon Cancer.

Research conducted by researchers from UK and Italy suggest that cannabis extract rich in cannabidiol (CBD) can be useful in treatment and prevention beginning and spread of colon cancer. This research was conducted using mice, and their results indicated that a combination of a botanical drug substance with CBD inhibited the growth of tumor cells and not the healthy cells. This action was linked to activation CB1 and CB2 receptors. They also investigated the effect of pure CBD on colon cancer and found that absolute CBD was capable of inhibiting tumor growth although it did so through activation of CB1 receptors only (Dorm 2018).

                                                                                     

Advantages and Disadvantages

Pain- Cannabinoids have been used in pain treatment inform of either herbal cannabis or cannabis extract for an extended period. Cannabinoids have been used as pain relievers in menstrual cramps, headache, and childbirth. As time goes, the application of cannabinoids in pain treatment continues to advance as their demands continue to increase (Carlisle et.al 2002). In the modern era, cannabinoid application is being suggested a variety of areas including relieving cancer pain. In chronic neuropathy, cannabinoids have been shown to be safe, relatively efficient and reasonable in the treatment of chronic neuropathic pain. On the contrary, evidence supporting the application of cannabinoids as the treatment for cancer pain is non-convincing. Studies by (Campbell 2001et.al), illustrated slight benefits and adverse effects hence limiting the dose in use.

Appetite- Information on cannabis and cannabinoid use in stimulation of appetite in cancer patients are not as conclusive as that found for pain and nausea. Application of cannabinoid in cachexia cancer patients has been found to be modestly effective. According to a Canadian study, oral administration of dronabinol improved the sense of taste and increased protein consumption (Pacher et.al 2011). However, this was not accompanied by weight gain. In non-cancer patients, there was improved appetite and weight gain as well. A study in dementia patients reported an increase in appetite, weight, and aggressive behavior after administration of dronabinol or placebo (Devinsky et.al 2015).

Nausea and vomiting-Cannabinoids were initially applied in nausea and vomiting treatments. Several studies proved that THC could be used to control nausea from chemotherapy and could eliminate emesis. However, the evidence to support cannabinoid control over nausea is not clear (Anderson et.al 2016).

 

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Effects of Cannabinoids on Pancreatic Cancer

Diagnosis of pancreatic cancer is complex and result in delayed detection. This is attributed to its anatomic localization and the nature of the symptoms. As such, by the time it is detected, a high percentage of the patients elicited metastasis infiltration in proximal lymphatic nodes, lungs, and the liver (Campbell 2001et.al). Only a few of the recognized tumors are rectifiable. In vitro, Activation of cannabinoid receptor CB2 has been found to induce pancreatic cancer cells apoptosis. In this study, the effects of cannabinoid in pancreatic cyst cells was investigated through determination of cannabinoids receptors expression in several differing human pancreatic cancer cell lines and human pancreatic cancer biopsies (Michalski et al. 2008).  mRNA levels of cannabinoid receptors were found to be very low and were not detectable. The effect of THC on cell efficacy was also tested. THC was confirmed to cause a dose-dependent reduction in the cells viability. Incubation with cannabinoid CB2 agonist was found to prevent the loss of cell viability by THC. THC was also found to cause apoptotic cell death. In another test, ceramide synthesized by de novo was found to be involved apoptosis of pancreatic cancer cells induced by THC (Tan et.al 2009).

Further, stress-regulated protein p8 was found to be part of apoptosis of pancreatic cancer cells caused by THC.  This protein is associated with several functions such as inducing apoptosis of pancreatic tumor cells. Additionally, regulation of p8 has been shown to increase with ceramide treatment (Caffarel et.al 2012). The participation of this protein in THC antiproliferative effects in pancreatic cancer cells was therefore tested. There was an increase in p8 mRNA levels after treating Miapaca2 cells with THC. Incubation with SR144528 or 1SP-1 was found to prevent this effect. Additionally, removal of p8 mRNA prevented apoptosis by THC in MiaPaCa2 cells (Martin 2018).

Additionally, p8 related genes that could contribute to the antitumor effect of THC were investigated. From this, several p8-dependent genes were identified and associated with apoptotic signaling. There was a similar increase in p8, TRB3, and ATF-4 mRNA levels after incubation with THC (Brett 2015).  Nevertheless, this was preventable by incubation with 1SP-1. Moreover, removal of p8 mRNA prevented increased regulation of TRB3 and ATF-4 and removal of ATF-4, or TRB3 mRNA inhibited apoptosis induced by THC. All these results illustrate that introduction of THC produced a p8 and ceramide controlled apoptotic response in pancreatic cancer cells that are involved in the increased regulation of these genes (Brett 2015).

Cannabinoid antitumor effects were also investigated in vivo models of pancreatic cancer. This was done by inducing tumors through injecting immunodeficient mice with MiaPaCa2 cells in PBS substituted with 0.1 glucose. When the tumors were at an average size, the animals were injected 15mg/kg/d THC for 15 days (Brett 2015).  This was seen to reduce established pancreatic tumor growth. Further, tumors were generated by intrapancreatic MiaCaPa2 cells injection to examine the cannabinoid antitumor effects in models resembling pancreatic cancer niche spreading. Due to the better bioavailability of synthetic WIN55, 212-2, it was chosen for the administration of i.p (Michalski et al. 2008).    Confirmation experiments were done for inducement of apoptosis in pancreatic cancer cells. WIN55, 212-2 administration, led to the effective reduction in intrapancreatic tumor growth as well as decreased tumor cells extension. This was an indication that treatment with cannabinoids affects both pancreatic tumor cell growth and spread. The mechanism of action in vivo in reducing tumor growth and spread was also examined. Tissues samples from the experiments were analyzed (Michalski et al. 2008).  It was observed that WIN55, 212-2 incubation elevated several apoptotic cells in tumor tissues but not in normal tissues. On the contrary, administration of cannabinoids significantly affects the amount of proliferating cells in the tumors. TRB3 proapoptotic protein expression was also analyzed (Rasmos 2006). This was essential since this protein associated with execution of apoptosis induced by endoplasmic reticulum stress.  Expression of TBR3 increased with treatment with WIN55, 212-2 in pancreatic cyst cells and not in healthy pancreatic cells. This shows that administration of cannabinoid stimulates apoptosis selectively in pancreatic tumor cells in vivo (Rasmos 2006).

Additionally, endocannabinoid systems are mainly involved in the growth of digestive cancers including pancreatic cancer, colon cancer, and liver cancer. Expressions of cannabinoid receptors are high in pancreatic tumor cells than in healthy pancreatic cells depicting the possibility of cannabinoid to contain cancer-promoting activity. Nevertheless, preclinical studies have shown that synthetic exogenous phyto-and endo-cannabinoids decrease angiogenesis, growth, and tumor incidences. Low cannabinoid concentrations have been proven to decrease cancer cell proliferation (Martinez-Martinez et al., 2015). However, more research is essential to discover the ability in vivo biphasic effects and identify the highest drug concentrations required in pancreatic cancer growth prevention. Additionally, more research is needed to demonstrate the efficacy of cannabinoids.

A study by (Michalski et al. 2008) evaluated cannabinoids receptors together with the endocannabinoid metabolizing fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGLL) enzymes immunoactivity.  Also, real-time quantitative analysis for MGLL, FAAH, RT-PCR and cannabinoid receptors was performed for both healthy and pancreatic cancer cells. Liquid chromatography was used to determine the level of endocannabinoids (Rasmos 2006).  In healthy human pancreatic cells, immunohistochemistry showed that immunoreactivity for FAAH and MGLL as well as islets and nerves were weak. The immunoactivity for FAAH and MGLL in pancreatic cancer tissues was high. Wide intrapancreatic nerves were found to be immunoreactive for FAAH and MGLL (Brett 2015).

In other studies, the combination of Gemcitabine (GEM) and cannabinoid in the treatment of pancreatic tumors enhanced intracellular production of ROS. In this connection, the antiproliferative effects of these two compounds are linked with the emerging oxidative stress. GEM stimulated cannabinoid receptor expression by an NF-jB-mediated mechanism. GEM was also found to influence CB1 and CB2 and mRNAs (Brett 2015).   CB and mRNAs GEM induction was regulated transcriptionally since their increase was affected by treatment with actinomycin D (ActD). Additionally, an increase of CB1 and CB2 through mRNA GEM mediation was prevented by NF-kB inhibitors and not free radical scavengers. IL-1, an inducer of NF-kB induces the expression of CB1 and CB2 which was affected by MG12 and abrogated by BAY (Donadelli et al. 2011). In combination, it is evident that NF-kB has a role in both cannabinoid receptor induction by GEM and antiproliferation effect by GEM/cannabinoid combination.

GEM also plays a part in inducing cannabinoids to produce ER stress. Some studies have reported that this stress is a mechanical action in antiproliferative effects of cannabinoids. The ability of GEM to enhance induction of ER stress by cannabinoids was investigated in a study by (Donadelli et al. 2011). mRNA expressions of ER stress sensors. This followed a single or combined treatment. From the results, SR1, GW or ACPA induced the three mRNA, and their levels were increased by GEM addition although the use of GEM alone was ineffective.  Autophagy by cannabinoids was enhanced by GEM through ROS- mediated mechanism (Donadelli et al. 2011). Further, antiproliferative activities of both GEM and cannabinoids were evaluated to determine whether apoptosis and cell cycle arrest had a role in it. GEM was found to induce apoptosis significantly but not cannabinoids. However, the results were partially affected by cannabinoids addition (Brett 2015).    GEM and cannabinoids were found to increase the number cells separately, but a combined treatment did not result in cell accumulation. This information depicts that a combination of both GEM and cannabinoids does not result in increased synergism through apoptotic or cell cycle modulation (Ramer 2010).

GEM and cannabinoids have been proven to inhibit the growth of pancreatic adenocarcinoma cells in vivo. This was investigated by use of nude mice. The tumor volume in mice treated with a combination of GEM and SR1 did not, but it increased in either GEM or SR1 treated mice.  However, body masses of the mice remained unchanged an indication that the treatment was non-toxic or did not produce any toxicity (Ramer 2010).

 

Conclusion

To facilitate understanding of cannabinoids therapeutic and translational ability in the treatment of cancer this paper examined the overall characteristics of cannabinoids and more specifically CBD and THC that are attributed to its role in cancer treatment. Most of the studies that are discussed show that endogenous cannabinoids, synthetic or cannabis extract are capable of reducing tumor invasion and growth. Additionally, few clinical studies evaluate cannabinoid ability in human models. However, these studies have depicted that cannabinoids can be active and safe against cancer. To ensure the appropriate potential of cannabinoids is determined future research should focus on clinical trials since they are currently not sufficient. Furthermore, it is the only approach that can provide the actual assessment of cannabinoid potential.

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