Journal of Pancreatic Cancer Journal of

Volume 5.1, 2019

DOI: 10.1089/pancan.2018.0019 Pancreatic Cancer

REVIEW ARTICLE Open Access

Potential Use of Cannabinoids for the Treatment

of Pancreatic Cancer
Golnaz Sharafi, Hong He, and Mehrdad Nikfarjam*

Abstract
Background: Cannabinoid extracts may have anticancer properties, which can improve cancer treatment outcomes.
The aim of this review is to determine the potentially utility of cannabinoids in the treatment of pancreatic cancer.
Methods: A literature review focused on the biological effects of cannabinoids in cancer treatment, with a focus
on pancreatic cancer, was conducted. In vitro and in vivo studies that investigated the effects of cannabinoids in
pancreatic cancer were identified and potential mechanisms of action were assessed.
Results: Cannabinol receptors have been identified in pancreatic cancer with several studies showing in vitro
antiproliferative and proapoptotic effects. The main active substances found in cannabis plants are cannabidiol
(CBD) and tetrahydrocannabinol (THC). There effects are predominately mediated through, but not limited to
cannabinoid receptor-1, cannabinoid receptor-2, and G-protein-coupled receptor 55 pathways. In vitro studies
consistently demonstrated tumor growth-inhibiting effects with CBD, THC, and synthetic derivatives. Synergistic
treatment effects have been shown in two studies with the combination of CBD/synthetic cannabinoid receptor
ligands and chemotherapy in xenograft and genetically modified spontaneous pancreatic cancer models. There
are, however, no clinical studies to date showing treatment benefits in patients with pancreatic cancer.
Conclusions: Cannabinoids may be an effective adjunct for the treatment of pancreatic cancer. Data on the
anticancer effectiveness of various cannabinoid formulations, treatment dosing, precise mode of action, and
clinical studies are lacking.
Keywords: cannabidiol; cannabinoids; pancreatic cancer; tetrahydrocannabinol

Introduction There are more than 60 phytocannabinoid entities

Pancreatic cancer is the fourth major cause of cancer found in cannabis plant extracts, among which there
death and is likely to become the second major cause of are currently two of main clinical interest: cannabidiol
cancer death after lung cancer by 2030, with an urgent (CBD) and tetrahydrocannabinol (THC).7,8 Endocan-
need to improve treatment outcomes.1,2 There has nabinoids are endogenous cannabinoids that include
been interest in the use of cannabinoids for the treat- anandamide (AEA) and 2-arachidonoylglycerol (2-AG),
ment of chemotherapy-related side effects such as ca- involved in a variety of physiological and cognitive pro-
chexia, lethargy, and nausea, but their potential use as cesses. Several synthetic cannabinoid compounds have
an anticancer agent is not well supported.3,4 Cannabi- been produced such as the aminoalkyl indole derivative
noids can be classified into plant-derived, endocannabi- WIN-55 that mimics THC and JWH-133, a potent CB2
noids and synthetic groups.5 receptor agonist that has anti-inflammatory effects. Pre-
Plant-derived cannabinoids are largely the product clinical studies have shown that certain synthetic cannabi-
of Cannabis sativa and Cannabis indica plant species.6 noids also have antiangiogenic and antitumor effects.5,9,10

Department of Surgery, University of Melbourne, Austin Health, Melbourne, Australia.

*Address correspondence to: Mehrdad Nikfarjam, MD, PhD, FRACS, Department of Surgery, University of Melbourne, Austin Health, LTB 8, Studley Road, Heidelberg,
Melbourne, Victoria 3084, Australia, E-mail: [email protected]

ª Golnaz Sharafi et al. 2018; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons
License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.

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Methods and catabolic enzymes such as the fatty acid amide hy-
A literature review of studies reporting on the cannabi- drolase (FAAH) system.17,20,21 Cannabinoid receptors
noids in cancer treatment was undertaken with a focus located on cell membranes are members of the G-
on pancreatic cancer. An electronic search was con- protein-coupled receptor (GPCR) family.22,23 Cannabi-
ducted in PubMed, MEDLINE, EMBASE, and Web noid receptor-1 (CB1) is found in moderate levels
of Science for articles published from November 1961 mainly in the brain and neural tissues and in lower
until September 2018. References of relevant literature levels in respiratory, digestive, and reproductive sys-
were reviewed to identify additional studies. In vitro tems and urinary tracts.22,24 It is mainly responsible
and in vivo studies that have investigated the effects for the psychological impacts of THC.18,25
of cannabinoids in pancreatic cancer, including poten- Cannabinoid receptor-2 (CB2) is mainly found in
tial mechanisms of action and signaling pathways, were peripheral organs, specifically rich in thymus, tonsils,
assessed. and spleen of immune system.9,26,27 CB2 sequence ap-
pears more preserved between species than CB1 recep-
Results and Discussion tor. Furthermore, there is a third putative human
Cannabis plants cannabinoid receptor, G-protein-coupled receptor 55
Cannabinoids are compounds extracted from two types (GPR55).21 Studies have shown that malignant cells
of plants, C. sativa and C. indica. Cannabis plants con- can alter the physiologic function of GPR55 and other
tain more than 400 chemical compounds, over 60 of GPCRs to enhance tumor growth and metastasis.28,29
them are phytocannabinoid entities, including delta- The endocannabinoids, 2-AG and AEA, are among
8-THC (d8-THC), cannabinol (CBN), cannabicyclol the main endogenous cannabinoids that stimulate
(CBL), cannabichromene (CBC), and cannabigerol CB1, CB2, and GPR55, and also act on transient recep-
(CBG);although THC and CBD are recognized as the tor potential ion channels, including transient receptor
two main substances, THC, CBD, and CBN have potential vanilloid (TRPV).20,21,24
mostly been used in different studies.8,11–13 These There are emerging data on other potential cannabi-
plants can be differentiated by their physical character- noid receptors, but to date, CB1, CB2, and GPR55 are
istics, C. indica has a short and dense plant structure considered the main cannabinoid targets.30
with dark green leaves, while C. sativa is a tall and
skinny plant with pale green appearance.14,15 THC and CBD and their effects on cancer
The C. sativa plants are also categorized into indus- THC is responsible for most of the psychological effects
trial hemp plants and medicinal plants. Hemp plants of cannabis.31 THC was first discovered to inhibit the
are grown for fiber and seed oil production, animal growth of lung adenocarcinoma cells in vitro and
feed, and for their high nutritional value.6 Both plants in vivo.5 THC binds to activate cannabinoid receptors,
contain the THC, but medicinal plants generally have a predominantly CB1 contained at high concentrations
higher content of THC that is concentrated in the plant in specific brain regions associated with emotions,
resin glands.16–18 Hemp plants are known to contain thinking, perception, memory, and coordination.32
low resin levels, while medical plants are high in THC works like the AEA neurotransmitter that is pro-
resin levels that cover the female’s flowering tops and duced in the body to regulate perception of pain, eat-
leaves. The THC concentration in flowering tops is sig- ing, and sleeping habits. Except for the initial relaxed
nificantly more than other parts of the plant.16,17,19 In state, it can bring about anxiety, delusions, hallucina-
addition, studies reveal that the THC:CBD ratio in tions, and emotions of happiness. Its effects begin im-
C. sativa is generally higher than C. indica. Therefore, mediately or 30 min after consumption, depending on
the euphoric and relaxing effects, after using C. sativa, the route of administration.33
are likely to be greater than with C. indica.15,16 CBD refers to that main cannabis compound with
desirable medical characteristics, without the stoning
Cannabinoid receptors effects.31 The discovery of CBD was in 1940, which is
The bodies’ endogenous opioid and cannabinoid sys- more than 20 years earlier than THC.34 It simulates
tems have remained unchanged for more than 500 mil- cannabinoid (CB1 and CB2) receptors indirectly,35
lion years of human evaluation.17 The endogenous and also involves several other receptor pathways that
cannabinoid system contains endocannabinoids, can- include but are not limited to TRPV1, GPR55, and per-
nabinoid receptors, second messengers, and anabolic oxisome proliferator-activated receptors.21,36 CBD in
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particular increases the susceptibility of tumor cells to Effects of cannabinoids on pancreatic cancer
the lymphokine-activated killer cells, which can result Effects of cannabis receptors. Studies showed that
in cell lysis.37 CB1 and CB2 receptors are expressed in pancreatic
Cannabis rich in CBD is less psychoactive than those cancer cells and have very low or nondetectable
rich in THC. Dominant CBD strains are more suitable mRNA levels in normal pancreatic cells.49 In a study
for applications in relieving spasms and pain, psycho- by Michalski et al.,49 the effects of cannabinoids in
sis, anxiety, inflammation, and some other conditions, pancreatic cells were investigated, with identification
with lesser effects on lethargy and lower likelihood of of cannabinoid receptor expression in several human
causing dysphoria.38 It can be of value in treating de- pancreatic cancer cell lines and human pancreatic can-
pression and some side effects that result from cancer cer biopsies. These results indicated that activation of
treatment.39 Overall, CBD is preferred for medical ap- cannabinoid receptors, particularly CB2, may induce
plications and has fewer health risks compared with pancreatic cancer cell apoptosis without affecting the
THC and is useful in negating some of the adverse ef- normal pancreas cells.
fects of THC.36,40 Michalski et al. also evaluated cannabinoid receptors
together with the endocannabinoid metabolizing FAAH
Mechanism of action and monoacylglycerol lipase (MGLL) enzymes in both
In vitro models for different cancer types have been normal (n:10) and pancreatic cancer cells from patients
utilized to elucidate mechanisms by which these canna- with resected pancreatic ductal adenocarcinoma (n:40).
binoids and endocannabinoids influence the prolifera- Immunohistochemistry staining showed that immuno-
tion, migration, and apoptosis of cancer cells.5 The reactivity for FAAH and MGLL was low in healthy
mechanisms to affect cancer cell proliferation, migra- human pancreatic cells, as well as islets and nerves
tion, and apoptosis by cannabinoids are complex and when compared with the immunoactivity for FAAH
can differ between cancer types.41–43 They can also in- and MGLL in pancreatic cancer tissues, although low
hibit tumor vascularization by altering the morphology levels of these enzymes in pancreatic cancer cells
of blood vessels and reducing blood vessel proangio- were correlated with shorter survival.
genic factors, including vascular endothelial growth Wide intrapancreatic nerves were found to be im-
factor.42,43 munoreactive for FAAH and MGLL. In addition,
Cannabinoids stimulate the production of ceramides there was a correlation between low CB1 receptor
by activation of ceramide synthase enzyme,44 which expression and prolonged survival for patients with
causes a downstream activation of a cascade that signals pancreatic cancer. CB2 receptor expression did not
through the extracellular regulated kinase (ERK) system correlate with survival. The levels of endocannabinoids
leading to cell cycle arrest and apoptosis. When CB1 AEA and 2-AG in serum of patients with pancreatic
and CB2 receptors are activated, the stress-regulated cancer cells in comparison with normal controls were
protein p8 controls the activating transcription factor similar.49
4 (ATF-4), C/EBP-homologous protein (CHOP), and
tribbles homologue3 (TRB3) expression. The ceramide- In vitro studies. Cytotoxic effects of cannabis in vitro
ERK signaling pathway is triggered to promote mito- occur through cannabinoid receptor-dependent and can-
chondrial intrinsic apoptosis via mechanisms that nabinoid receptor-independent mechanisms.50,51 A
have not yet been recognized.45 An increase in ceramide study by Fogli et al. showed that cannabis receptor
can also activate the p38 mitogen-activated protein ki- binding by synthetic receptor agonists, WIN-55,212-2
nase pathway leading to apoptosis through several (CB1 and CB2), ACEA (CB1), and JWH-015 (CB2),
mechanisms.10,42,46 caused a substantial cell death of MiaPaCa-2 cell.52
Activation of CB1 or CB2 receptors can also inhibit The authors also demonstrated that the CB1 inverse
the activity of adenylyl cyclase and decreases the levels agonist (AM251) induced apoptosis and affected tran-
of cyclic adenosine monophosphate47 and the activa- scriptional genes via the JAK/STAT and MAPK signal-
tion of protein kinase A. As a result, there is a decrease ing network in MiaPaCa2 pancreatic cancer cells,
in gene transcription causing apoptosis.41 Activation of acting through CB1 receptor-independent pathways.52
cannabinoid receptors can also promote cancer cell In addition, AM251 synergically increased the antican-
survival and inhibit apoptosis through PI3K/PKB path- cer effect of pyrimidine analog chemotherapy agent, 5-
ways, implicated in cell survival.48 fluorouracil.52
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It is possible, however, that these agents have CB1 A recent study showed that the GPR55 receptor, reg-
agonistic effects at higher concentrations, in keeping ulated by tumor suppressor p53, may have a crucial
with findings reported for a structurally similar ligand, role in pancreatic cancer development, via cell cycle
SR141716A.53,54 regulation and MAPK signaling pathways.61 CBD
The CB1 and CB2 selective agonists, arachidonyl- binds to the GPR55 receptor and blocks its activity.
cyclopropylamide (ACPA) and GW, inhibited prolifer- Cell growth, cell cycle progression, and MAPK signal-
ation and invasion of Panc1 cells, respectively.55 ACPA ing in ASPC1, HPAFII, BXPC3, and PANC1 pancre-
and GW through activating the CB1 and CB2 receptors atic cancer cell lines were inhibited by treatment with
stimulated 5’ adenosine monophosphate-activated pro- the GPR55 antagonist CID16020046 (CID) and CBD.
tein kinase activation via a reactive oxygen species Moreover, HPAFII and PANC1 cell growth was re-
(ROS)-dependent escalate of AMP/ATP ratio, causing duced to a greater extent with the combination of
cell autophagy and cell growth inhibition.55,56 CBD and gemcitabine, compared with either treatment
Ceramide synthesized by de novo synthesis was found alone.61 This study demonstrated that the gemcitabine
to be involved in the apoptosis of pancreatic cancer cells effects on pancreatic cancer cells might be potentiated
induced by THC.57 THC has been shown to cause a by inhibition of GPR55.
dose-dependent reduction in cell viability by inducing
apoptotic cell death.58 The stress-regulated protein p8 In vivo studies. Pre-clinical studies on various cancers
was involved in the apoptosis of pancreatic cancer have shown that synthetic exogenous, endo-, and phy-
cells caused by THC. This protein has been shown to in- tocannabinoids decrease angiogenesis, growth, and
crease with ceramide treatment and has powerful antitu- tumor cell migration and induction of apoptosis in can-
mor effects.59 There was an increase in p8 mRNA levels cer cells.9,62 The antitumor effects of cannabinoids were
in MiaPaca2 pancreatic cancer cells treated with THC, also investigated in in vivo models of pancreatic cancer.
which was blocked by a potent antagonist of CB2 Xenografted MiaPaca2 pancreatic tumor growth was
(SR144528). Knockdown of p8 mRNA prevented inhibited by THC (15 mg/kg/day) treatment.58 The
apoptosis induced by THC in MiaPaCa2 cells.59 pancreatic tumor growth in an orthotropic model was
Furthermore, several p8-dependent genes, including also inhibited by the synthetic cannabinoid receptor
the endoplasmic reticulum (ER) stress-related gene agonist WIN55212,2.49 WIN55212,2 also induced apo-
TRB3 (a novel ER stress-inducible gene), CHOP, and ptosis in pancreatic cancer cells through possibly the
ATF-4, were identified and associated with apoptotic activation of TRB3, which is a proapoptotic protein re-
signaling. The mRNAs of TRB3, CHOP, and ATF-4 sponsible for the apoptosis induced by ER stress.
were increased to a similar degree as p8 by THC treat- WIN55212,2 increased the expression of down-
ment.45 Moreover, removing the p8 mRNA prevented stream ER stress-related targets involved with apoptosis
upregulation of TRB3, CHOP, and ATF-4. THC induced in pancreatic cancer but not in healthy pancreatic cells,
a p8- and ceramide-mediated apoptotic response in pan- indicating that cannabinoid stimulates apoptosis selec-
creatic cancer cells through upregulation of these genes.45 tively in pancreatic cancer cells.58
The combination of gemcitabine and cannabinoid re- The route of cannabinoid administration has signifi-
ceptor agonists in the treatment of pancreatic cancer en- cant effects on pharmacokinetics, bioactivity, bioavail-
hanced intracellular production of ROS, resulting in ability, and effectiveness of drugs. Cannabinoids are
antiproliferative effects. Gemcitabine stimulated the water insoluble and cannot be administered intrave-
mRNAs of both CB1 and CB2 via an NF-jB-mediated nously. In addition, cannabinoids are partially degraded
mechanism.60 Nuclear factor-kappaB (NF-jB) inhibi- by the stomach acids; as a result, oral administration
tors, MG12 and BAY, blocked gemcitabine-stimulated may not be the most effective route for cancer treat-
increase of either CB1 or CB2 mRNAs, while interleukin ment.63 The inhalation route of cannabinoids combined
(IL)-1, an inducer of NF-jB, increased the expression of with nanomaterials may be useful for targeting lung can-
CB1 and CB2.60 Gemcitabine also plays a part in cer, but the effectiveness in treating other sites is less cer-
cannabinoid-induced ER stress and antiproliferation.60 tain.64 Intratumor (IT) administration of low doses of
Cannabinoid-induced autophagy was enhanced by gem- cannabinoids enhances the effectiveness of drug.4,65,66
citabine through ROS-mediated mechanism.60 In addi- A study by Yasmin-Karim et al. revealed that a supe-
tion, cannabinoids substantially increase the apoptotic rior pancreatic cancer treatment outcome could be
effect of gemcitabine.60 achieved using the combination of cannabinoids and
Sharafi, et al.; Journal of Pancreatic Cancer 2018, 5.1 5
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radiotherapy.7 Similar findings have been demonstrated may prevent progression from chronic pancreatitis to
in a brain glioma cancer model.67 Improved survival was pancreatic cancer.
also demonstrated with IT administration of cannabi-
noids into subcutaneously implanted murine PANC-02 Conclusion
pancreatic cancers measuring 6 mm in maximum dimen- Endogenous cannabinoids, synthetic or cannabis ex-
sion.7 Furthermore, treating Kras, P53, and Cre mice with tracted from plants, can reduce tumor invasion and
a combination of CBD (100 mg/kg) by daily intraperito- growth, induce tumor cell death, and inhibit tumor
neal (IP) administration and gemcitabine (100 mg/kg) by angiogenesis via cannabinoid receptor or receptor-
IP administration every 3 days, IP after 80 days of age independent pathways. Cannabinoid receptors appear to
prolonged the animal survival three times more than ve- be highly expressed in pancreatic cancer compared with
hicle or gemcitabine treatment alone.61 normal pancreatic tissue. CBD and THC appear to have
Similar findings were shown in a study by Donadelli antiproliferative and proapoptotic effects. CBD in a clini-
et al., in which a CB1 binding ligand SR141716 (SR1) cally relevant pancreatic cancer model improved survival
combined with gemcitabine reduced tumor growth outcomes when combined with gemcitabine. Clinical
greater than either agent alone.60 Based on their studies on the utility of cannabinoids in the treatment of
in vitro finding, the authors found that an increase in pancreatic cancer are lacking and urgently needed.
ROS and autophagy pathways may explain the ob-
served synergistic effects in vivo.60 SR1 has been uti- Acknowledgment
lized as an antiobesity agent and is considered a We acknowledge Pancare Foundation (www.pancare
reverse agonist that possessed agonist activity at higher .org.au) for supporting pancreatic cancer research in
concentrations.53 The use of SR1 as an anticancer agent the Department of Surgery.
in the clinical situation is, however, unknown, as the
drug has been withdrawn from the worldwide market Author Disclosure Statement
due to unacceptable psychiatric side effects. No competing financial interests exist.

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Sharafi, et al.; Journal of Pancreatic Cancer 2018, 5.1 7
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ROS ¼ reactive oxygen species
Cite this article as: Sharafi G, He H, Nikfarjam M (2019) Potential use THC ¼ tetrahydrocannabinol
of cannabinoids for the treatment of pancreatic cancer, Journal of TRB3 ¼ tribbles homologue3
Pancreatic Cancer 5:1, 1–7, DOI: 10.1089/pancan.2018.0019. TRPV ¼ transient receptor potential vanilloid

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