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The plant Cannabis sativa L. has been used as an herbal remedy for centuries and is the most important source of phytocannabinoids. The endocannabinoid system (ECS) consists of receptors, endogenous ligands (endocannabinoids) and metabolizing enzymes, and plays an important role in different physiological and pathological processes. Phytocannabinoids and synthetic cannabinoids can interact with the components of ECS or other cellular pathways and thus affect the development/progression of diseases, including cancer. In cancer patients, cannabinoids have primarily been used as a part of palliative care to alleviate pain, relieve nausea and stimulate appetite. In addition, numerous cell culture and animal studies showed antitumor effects of cannabinoids in various cancer types. Here we reviewed the literature on anticancer effects of plant-derived and synthetic cannabinoids, to better understand their mechanisms of action and role in cancer treatment. We also reviewed the current legislative updates on the use of cannabinoids for medical and therapeutic purposes, primarily in the EU countries. In vitro and in vivo cancer models show that cannabinoids can effectively modulate tumor growth, however, the antitumor effects appear to be largely dependent on cancer type and drug dose/concentration. Understanding how cannabinoids are able to regulate essential cellular processes involved in tumorigenesis, such as progression through the cell cycle, cell proliferation and cell death, as well as the interactions between cannabinoids and the immune system, are crucial for improving existing and developing new therapeutic approaches for cancer patients. The national legislation of the EU Member States defines the legal boundaries of permissible use of cannabinoids for medical and therapeutic purposes, however, these legislative guidelines may not be aligned with the current scientific knowledge.
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1
BOSNIAN JOURNAL of
Basic Medical Sciences WWW.BJBMS.ORG
INTRODUCTION
e first discovered and most important source of can-
nabinoids was the plant Cannabis sativa L., which has been
used as an herbal remedy for centuries. e earliest archae-
ological evidence of cannabis medical use dates back to the
Han Dynasty in ancient China, where it was recommended
for rheumatic pain, constipation, disorders of the female
reproductive tract, and malaria among other conditions. In
traditional Indian Ayurvedic medicine, cannabis was used to
treat neurological, respiratory, gastrointestinal, urogenital, and
various infectious diseases []. e plant was also cultivated
in other countries in Asia as well as in Europe, especially for
making ropes, clothes/fibres, food and paper []. In Western
medicine, the use of cannabis was notably introduced by
the work of William B. O’Shaughnessy (an Irish physician)
and Jacques-Joseph Moreau (a French psychiatrist) in the
mid-thcentury, who described positive effects of cannabis
preparations, including hashish (the compressed stalked resin
glands), on pain, vomiting, convulsions, rheumatism, tetanus
and mental abilities. Cannabis was recognized as a me dicine in
the United States (US) Pharmacopoeia from , in the form
of tinctures, extracts and resins. However, in the beginning of
the thcentury, cannabis use decreased in Western medicine
due to several reasons: increased use as a recreational drug,
abuse potential, variability in the quality of herbal material,
individual (active) compounds were not identified and alter-
native medications, with known efficacy, were introduced to
treat the same symptoms [,]. In , as the result of many
legal restrictions, cannabis was removed from the American
Pharmacopoeia and considered to be in the same group as
Cannabinoids in cancer treatment: erapeutic potential
and legislation
Barbara Dariš1*, Mojca Tancer Verboten2, Željko Knez1,3, Polonca Ferk4
Department of Cell Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Maribor, Maribor, Slovenia, Department
of Labour Law, Faculty of Law, University of Maribor, Maribor, Slovenia, Laboratory for Separation Processes and Product Design, Faculty
of Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia, Institute for Biostatistics and Medical Informatics,
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
ABSTRACT
e plant Cannabis sativa L. has be en used as an herbal remedy for centuries and is the most important source of phytocannabinoids. e endo-
cannabinoid system (ECS) consists of receptors, endogenous ligands (endocannabinoids) and metabolizing enzymes, and plays an important
role in different physiological and pathological processes. Phytocannabinoids and synthetic cannabinoids can interact with the components
of ECS or other cellular pathways and thus affect the development/progression of diseases, including cancer. In cancer patients, cannabinoids
have primarily been used as a part of palliative care to alleviate pain, relieve nausea and stimulate appetite. In addition, numerous cell culture
and animal studies showed antitumor effects of cannabinoids in various cancer types. Here we reviewed the literature on anticancer effects of
plant-derived and synthetic cannabinoids, to better understand their mechanisms of action and role in cancer treatment. We also reviewed the
current legislative updates on the use of cannabinoids for medical and therapeutic purposes, primarily in the EU countries. In vitro and in vivo
cancer models show that cannabinoids can effectively modulate tumor growth, however, the antitumor effects appear to be largely dependent
on cancer type and drug dose/concentration. Understanding how cannabinoids are able to regulate essential cellular processes involved in
tumorigenesis, such as progression through the cell cycle, cell proliferation and cell death, as well as the interactions between cannabinoids and
the immune system, are crucial for improving existing and developing new therapeutic approaches for cancer patients. e national legislation
of the EU Member States defines the legal boundaries of permissible use of cannabinoids for medical and therapeutic purposes, however, these
legislative guidelines may not be aligned with the current scientific knowledge.
KEY WORDS: Cannabinoids; antitumor effects; signaling pathways; legislation
DOI:http://dx.doi.org/./bjbms.. Bosn J Basic Med Sci. xxxx;xx(x):1-10. © 2018 ABMSFBIH
*Corresponding author: Barbara Dariš, Department of Cell Biology,
Institute of Biomedical Sciences, Faculty of Medicine, University of
Maribor, Taborska , SI- Maribor, Slovenia.
E-mail: barbara.daris@um.si.
Submitted:  April /Accepted:  May 
REVIEW ARTICLE
Barbara Dariš, et al.: Cannabinoids and cancer
2
other illicit drugs []. Consequently, the exploration of med-
ical uses of cannabis has been significantly slowed down
for more than a half of century. In , a step forward was
made with the inclusion of a monograph of Cannabis spp. in
the American Herbal Pharmacopoeia []. Moreover, the cur-
rent legislative changes in the European Union (EU), US and
Canada that allow cannabis for medical and/or recreational
use, the progress in scientific research and public awareness
on the benefits of medical cannabis all contributed to the ris-
ing interest in the therapeutic potential of cannabinoids [,].
In recent years, cannabinoids have been extensively stud-
ied for their potential anticancer effects and symptom man-
agement in cancer patients [-]. One of the first studies
describing antineoplastic activity of cannabinoids was pub-
lished in  []. Potential antitumor activity of plant-derived
or phytocannabinoids, e.g., (−)-trans-∆-tetrahydrocannabi-
nol (THC), cannabinol (CBN), ∆-THC, cannabidiol (CBD)
and cannabicyclol (CBL), as well as of synthetic cannabinoids,
such as WIN-,-, is the focus of current research [,,].
In the s, the main components of the endocannabinoid
system (ECS) were identified as follows: (i) two types of cannabi-
noid (CB) receptors, CB and CB receptor; (ii) two main endog-
enous ligands (endocannabinoids) in mammals, anandamide or
N-arachidonoyl ethanolamine (AEA) and -arachidonoylglyc-
erol (-AG); and (iii) endocannabinoid metabolic enzymes,
fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase
(MAG lipase). FAAH is the primary catabolic enzyme for fatty
acid amides (FAAs), a class of bioactive lipids including AEA,
while MAG lipase is a key enzyme in the hydrolysis of -AG
[-]. Subsequent studies demonstrated the important role of
the ECS and endocannabinoids in different physiological and
pathological processes, such the regulation of excitatory and
inhibitory synaptic transmission in the central nervous system
(CNS), food intake, nociceptive signaling, analgesia, immuno-
modulation, inflammation, and cancer cell signaling [-].
In cancer patients, cannabinoids have primarily been used
as a part of palliative care to alleviate pain, relieve nausea and
stimulate appetite [,]. In addition, numerous cell culture
and animal studies showed antitumor effects of cannabi-
noids and suggested new therapeutic opportunities for can-
cer patients []. However, recent research also emphasizes
the importance of safety measures when using cannabinoids,
since these compounds can potentially impair cognitive func-
tions, especially in adolescents [].
e aim of this article is to review the relevant literature
on anticancer effects of plant-derived and synthetic cannabi-
noids, to increase our understanding of their potential mecha-
nisms of action and possible role in cancer treatment. We also
reviewed the current legislative updates on the use of canna-
binoids for medical and therapeutic purposes, primarily in the
EU countries.
MOLECULAR BASIS FOR
CANNABINOID TREATMENT OF
CANCER
e role of the endocannabinoid system in cancer
Endocannabinoids interact with different types of recep-
tors, including the two Gi/o-coupled CB receptors, CB and
CB []. While CB receptors are mainly located in the
CNS and, to a lesser degree, in some peripheral tissues, CB
receptors are primarily expressed on the surface of immune
cells[]. Due to the low expression of CB receptors in the
CNS they represent a promising pharmacological target, as
selective CB ligands potentially would not have psychotropic
effects []. In addition, other CB receptor types and isoforms
or completely different pharmacological targets of cannabi-
noids have been described, for example transient receptor
potential vanilloid receptor  (TRPV), orphan G-protein
coupled receptor (GPR), peroxisome proliferator-activated
receptors (PPARs) [,], transient receptor potential melas-
tatin  (TRPM), TRP vanilloid  (TRPV) and TRP ankyrin
 (TRPA) channel []. It is important to note that cannabi-
noids may also exert their antitumor effects independent of
the CB receptors, for example as demonstrated in human pan-
creatic cancer cell line MIA PaCa- [].
e biological role of the ECS in cancer pathophysiology
is not completely clear [] but most studies suggest that CB
receptors and their endogenous ligands are upregulated in
tumor tissue [,,,-,,] and that the overexpres-
sion of ECS components (i.e.,receptors, ligands, and enzymes)
correlates with tumor aggressiveness [-]. However, a
tumor-suppressive role of ECS was also indicated by some
studies, e.g.,the upregulation of endocannabinoid-degrading
enzymes was observed in aggressive human cancers and can-
cer cell lines []. Moreover, experimental studies showed that
the activation of CB receptors by cannabinoids is antitumor-
igenic in most cases, i.e., it inhibits tumor cell proliferation,
induces apoptosis in vitro, and blocks angiogenesis and tumor
invasion/metastasis in vivo [,,,]. e effects of CB
receptor (over)expression in selected human tumor cell lines
are described in more detail in Table.
Antitumor effects of cannabinoids
By targeting the ECS, cannabinoids affect many essential
cellular processes and signaling pathways which are crucial for
tumor development [,,]. For example, they can induce
cell cycle arrest, promote apoptosis, and inhibit proliferation,
migration and angiogenesis in tumor cells (Figure ) [,].
In addition to CB receptor-mediated (CB and CB recep-
tors) cannabinoid effects, it appears that these processes
can also be CB receptor-independent (e.g.,through TRPV,
3
Barbara Dariš, et al.: Cannabinoids and cancer
-hydroxytryptamine [-HT], or nicotinic acetylcholine
receptor [nAChR] among others) [], suggesting that molec-
ular mechanisms underlying the antitumor activity of can-
nabinoids are even more complex than originally thought.
Moreover, it is expected that future studies will discover novel
molecular targets of cannabinoids [].
e ability of plant-derived and synthetic cannabinoids
to control cancer cell growth, invasion, and death has been
demonstrated in numerous experimental studies using cancer
cell lines and genetically engineered mouse models. Also, differ-
ent types of cannabinoids may have different modes of action.
For example, a phytocannabinoid THC promotes apoptosis in
a CB-receptor dependent manner, while CBD exerts this effect
independently of CB/CB receptors and possibly includes the
activation of TRPV receptor, at least in some cancer types.
Also, some CB receptor agonists are less efficient in promoting
cancer cell death although they demonstrate higher affinity for
CB receptors than THC, such as synthetic CB receptor agonist
WIN-,-. Better understanding of homo-or hetero-oligo-
merization of CB receptors, their interactions with lipid rafts
for example, and mechanisms of selective G-protein coupling
may clarify these differences []. Finally, because molecular
changes are tumor-specific in most cases (i.e.,the presence of
intra-and inter-tumor heterogeneity), CB-receptor mediated
antitumor effects largely depend on the type of cancer that is
being investigated and characteristics of derived tumor cell
line, including the donor characteristics, tumor site of origin
and hormonal responsiveness [-].
PLANT-DERIVED CANNABINOIDS
AND THEIR ANTITUMOR ACTIVITY
Phytocannabinoids are a group of C terpenopheno-
lic compounds predominately produced by the plants from
the genus Cannabis. Different resources indicate that there
are more than  different cannabinoids together with their
breakdown products, although some report that >  com-
pounds is a more accurate estimation. Among these, the most
abundant are THC, CBD, CBN and cannabichromene (CBC)
followed by ∆-THC, cannabidiolic acid (CBDA), cannabidi-
varin (CBDV) and cannabigerol (CBG). e highest content
of cannabinoids is located in the flowering tops of the plant
and small, young leaves around the flowers [].
Pharmacologically, THC is a partial agonist at CB and CB
receptor with inhibitory constant (Ki) of . nM for CB and
. nM for CB []. ∆-THC is a stable isomer of THC with
similar Ki []. e most studied non-psychotropic phytocan-
nabinoid is CBD which does not have psychotomimetic activ-
ity. CBD has a low affinity for CBand CB; it was suggested
that it acts as an antagonist of CB/CB agonists but also as
TABLE1. Expression of cannabinoid (CB) receptors in selected human cancer types
Cancer cell type Regulation of CB1/CB2Mechanisms and other relevant circumstances Reference
Breast cancer
Elevated CB2 receptor expression in
HER2+breast tumors.
HER2 induces CB2 expression activating ELK1(ERK/MAPK cascade);
activated pro-oncogenic signaling through tyrosine kinase c-Src. [28,29]
Presence of TRPV1 in human breast
adenocarcinoma cell line(MCF-7).
TRPV1 agonists/antagonists induce significant inhibition of MCF-7
cell growth. [30]
Prostate cancer
Elevated CB1 receptor expression. Activation of Akt signaling pathway was proposed. Increased CB1 and
FAAH levels correlate with severity of the disease.
[31-34]
[35,36]
Expression of CB1 and CB2 receptor
significantly higher in human prostate
cancer.
Additionally: Presence of TRPV1 and TRPA1 in all prostate cancer
cells(except LNCaP cells), TRPV2 in DU-145 and PC-3 cells only,
TRPM8 in AR-dependent prostate cell lines(e.g., LNCaP).
[37-39]
Expression of CB1 and CB2 receptor
significantly higher in human prostate
cancer.
Expression of GPR55 in
PC-3 and DU-145 cell lines has been reported, mediating effects of LPI. [40]
Chemically induced
hepatocellular
carcinoma
Upregulation of CB1 receptors. Diethylnitrosamine induced liver cancer. [41]
Hepatocellular
carcinoma Overexpression of CB1 and CB2 receptors. Overexpression of CB1 and CB2 receptors is associated with improved
prognosis.
[42]
Non-small cell lung
cancer Overexpression of CB1 and CB2 receptors. Activation of Akt signaling pathway, MMP9 expression and activity. [43]
Chronic lymphocytic
leukemia Overexpression of CB1 and CB2 receptors. CB1 receptor expression correlated with high-risk markers. [44]
Pancreatic cancer
CB1 and CB2 receptors expressed in
normal and pancreatic cancer cells(higher
expression of CB1).
Cannabinoids induced apoptosis via CB2 receptor(ceramide
dependent pathway). [45-47]
Melanoma CB2 is overexpressed in human melanoma
tissues and cell lines. Not reported. [48]
HER2: Human epidermal growth factor receptor 2; ELK1: ETS domain-containing protein; c-Src: Tyrosine-protein kinase Src;
ERK: Extracellular-signal-regulated kinase; MAPK: Mitogen-activated protein kinase; TRPV1: Transient receptor potential vanilloid receptor 1; Akt: Protein
Kinase B; FAAH: Fatty acid amide hydrolase; TRPA1: Transient receptor potential ankyrin 1; GPR55: Orphan G-protein coupled receptor 55; AR: Androgen
receptor; LPI: Lysophosphatidylinositol; MMP9: Matrix metallopeptidase 9
Barbara Dariš, et al.: Cannabinoids and cancer
4
a CB inverse agonist (an inverse agonist binds to the same
receptor-binding site as an agonist and it does not only antag-
onize the effects of the agonist but exerts the opposite effect).
Other mechanisms of action of CBD, that are independent
of CB receptors, include FAAH inhibition, inhibition of AEA
reuptake, it acts as an agonist at PPARγ, TRPV, TRPA and
an antagonist at GPR and TRPM (Table). CBN is a weak
partial agonist at CB (Ki of  nM) and CB(Ki of . nM);
CBG is a potent TRPM antagonist, TRPV and TRPA ago-
nist, and CB partial agonist; while CBC is a potent TRPA ago-
nist and weak inhibitor of AEA reuptake [].
Plant-derived cannabinoids are approved only for some
indications, but additionally have been used off-label. For
example, a standardized alcoholic cannabis extract nabixi-
mols, which has the THC:CBD ratio of : and is available as
an oromucosal spray, was approved in Germany for the treat-
ment of moderate to severe refractory spasticity in multiple
sclerosis. Examples of off-label use of this medication are of
chronic pain in several medical conditions and symptomatic
treatment of selected neuropsychological disorders (e.g.,anx-
iety and sleeping disturbances). Common side effects of can-
nabinoids are tiredness and dizziness (in more than  of
patients), dry mouth, and psychoactive effects among others.
Nevertheless, tolerance to these side effects develops within
a short time in almost all cases. Withdrawal symptoms are
rarely observed in the therapeutic setting [].
An exciting area of research is the technological improve-
ment of existing pharmaceutical formulations, especially
the development of new cannabis-based extracts. Romano
etal.[] found that a CO extracted cannabis extract, with a
high content (.) in -tetrahydrocannabivarin (THCV),
inhibits nitrite production induced by lipopolysaccharides
(LPS) in murine peritoneal macrophages, and thus may have a
potential to modulate the inflammatory response in different
FIGURE 1. Example of different signaling pathways induced by cannabinoids in cancer cells [46,51,53-55]. By targeting the endocanna-
binoid system (ECS), cannabinoids affect many essential cellular processes and signaling pathways which are crucial for tumor develop-
ment. For example, they can induce cell cycle arrest, promote apoptosis, and inhibit proliferation, migration and angiogenesis in tumor
cells. AEA: Anandamide; 2-AG: 2-Arachidonoylglycerol; Akt: Protein Kinase B; AMPK: 5’ adenosine monophosphate-activated protein
kinase; Bad: Bcl-2-associated death promoter; Bax: Apoptosis regulator; CaMKK: Calcium/calmodulin-dependent protein kinase kinase;
Cdk 2: Cyclin-dependent kinase 2; CHOP: C/EBP homologous protein; CycD: Cyclin D; Cyc E: Cyclin E; ELK1: ETS domain-containing pro-
tein; ERK: Extracellular-signal-regulated kinase; FAAH: Fatty acid amide hydrolase; GPR55: Orphan G-protein coupled receptor 55; MAG
lipase: Monoacylglycerol lipase; MAPK: Mitogen-activated protein kinase; p8: Candidate of metastasis 1; p21: Cyclin-dependent kinase
inhibitor 1; p27: Cyclin-dependent kinase inhibitor 1B; PI3K: Phosphoinositide 3-kinase; PKA: Protein kinase A; ROS: Reactive oxygen spe-
cies; TRPV1: Transient receptor potential vanilloid receptor 1; TRPV2: Transient receptor potential vanilloid receptor 2; TRPM8: Transient
receptor potential melastatin 8; mTORC1: Mammalian target of rapamycin complex 1; mTORC2: Mammalian target of rapamycin com-
plex 2; TRIB3: Tribbles homolog 3.
Arachidonic acid + ethanolamine
Arachidonic acid + glycerol
Plant-derived / synthetic cannabinoids
AEA
2-AG
FAAH
ROS
MAG lipase
Gio
C
Ceramide
CB1 / CB2
receptor N
GPR55TRPV1, TRPV2
TRPM8
C
N
PKA
MAPK activation
(P38/MAPK, JNK and ERK1/2)
Adenylate
cyclase
Proapoptotic proteins
(BAD, Bax)
( cAMP)
Antiapoptotic proteins
(Bcl-2)
Inhibition
Activation
Antitumor effect
APOPTOSIS
AUTOPHAGY
INHIBITED CELL PROLIFERATION
CELL CYCLE
ARREST
Cyc D
Cyc E
cdk2
cdc2
AMPK
ERK1/2
CaMKK
ER stress
mTORC2
mTORC1
TRIB3
P13K
Akt
p27
p21
p8
CHOP
β
5
Barbara Dariš, et al.: Cannabinoids and cancer
disease conditions []. Another study compared in vitro anti-
oxidant activity and gene expression of antioxidant enzymes
between ethanol and supercritical fluid (SF) extracts of dehu-
lled hemp seed. SF extract exhibited higher radical scavenging
activities compared to ethanol extract. Both extracts upreg-
ulated the expression of the antioxidant enzymes superoxide
dismutase (SOD), glutathione peroxidase (GPx), and catalase
(CAT) in human hepatoma (HepG) cells challenged with
HO, and this effect was greater for SF extracts at the concen-
tration of  g/mL [].
Different plant-derived cannabinoids and cannabis-based
pharmaceutical drugs have been the subject of intensive research
for their potential antitumor activity, especially in cancer cells
that overexpress CBand/or CB receptors compared to normal
tissues []. Many studies were conducted in different cell lines
with cannabis extracts or individual isolated compounds and the
results are sometimes confounding, because efficient anticancer
effects, such as decreased proliferation of cancer cells, activation
of apoptosis, inhibition of cell migration and decreased tumor
vascularization are mainly recorded in breast, prostate and gli-
oma cancer cell lines. In contrast, protumorigenic activity of
natural cannabinoids, i.e.,increased cell proliferation, has been
reported in lung, breast, and hepatoma cell lines []. It appears
that the balance between protumorigenic and antitumor effects
of cannabinoids critically depends on their concentration,
among other factors. For example, Hart et al. [] showed that the
treatment of glioblastoma U-MG and lung carcinoma NCI-
H cell line with nanomolar concentrations of THC (instead
of commonly used micromoral concentrations) led to increased
cell proliferation. e authors also emphasized that nanomolar
concentrations of THC are more likely to be detected in the
serum of patients after drug treatment []. erefore, in cancer
therapy, it is very important to consider the risk of acceleration of
tumor growth due to the concentration-dependent proliferative
potential of cannabinoids [].
In addition to THC, CBD is another plant-derived can-
nabinoid that has been extensively studied for its potential
antitumor effects [,-]. In a panel of human prostate
cancer cell lines, Sharma et al. [] showed that CBD is a
potent inhibitor of cancer cell growth, while this potency
was significantly lower in non-cancer cells. Moreover, CBD
downregulated CB, CB, vascular endothelial growth fac-
tor (VEGF) and prostate-specific antigen (PSA) in prostate
cancer cells, as well as pro-inflammatory interleukin (IL)-
and IL- in LPS-stimulated dermal fibroblasts, suggesting its
anti-inflammatory properties []. Other studies showed that
CBD preferentially inhibited the survival of breast cancer cells
by inducing apoptosis and autophagy [] and inhibited prolif-
eration and cell invasion in human glioma cell lines [].
e expression of CB and CB receptors on immune cells
suggests their important role in the regulation of the immune
system. Recently, it was demonstrated that the administration
TABLE2. Antitumor activity of selected plant-derived cannabinoids in different cancer cell lines
Cancer cell line Compound Effect Major mechanism Reference
Human breast cell lines
MCF-7 THC Decreased proliferation. Not reported. [63]
MDA-MB-231 CBD Reduced cell viability. Induced
apoptosis and autophagy.
Induced endoplasmic reticulum stress, inhibits
Akt and mTOR signaling. [65]
Human glioma cell lines
U373-MG,
NCI-H292 THC Increased proliferation. rough TACE/ADAM17. [64]
U87-MG,
T98G CBD Inhibits proliferation and invasion. Downregulation of ERK and Akt signaling
pathway, inhibits HIF-1α. [66]
SF-126,
U251
THC+CBD(enhances THC
inhibitory effect)
Synergic inhibition of cell
proliferation.
Modulation of cell cycle, induction of ROS,
apoptosis, modulation of ERK, caspase activities.
[68]
Human prostate cancer cell lines
LNCaP Cannabis extract(CBD enriched) Decreased cell viability. Decreased AR mRNA expression, decreased
mRNA expression of CB1 and CB2 receptor,
PSA reduction, apoptosis.
[39]
PC-3 Cannabis extract(CBD enriched) Decreased cell viability. Not reported. [39]
DU-145
CBD, CBC, CBG,
THC(according to decreased
potency)
Decreased cell viability. Induced apoptosis(intrinsic apoptotic
pathways).
[39]
LNCaP THC, CBD, CBC , CBG(according
to decreased potency) Decreased cell viability. Induced apoptosis, activation of TRPM8. [39]
Human pancreatic cancer cell lines
Capan-2,
PANC-1,
MIA PaCa-2,
BxPC-3
THC Decreased cell viability Induction of p8-ATF-4-TRIB3 pro-apoptotic
pathway.
[47]
THC: (−)-trans-9-tetrahydrocannabinol; CBD: Cannabidiol; CBC: Cannabichromene; CBG: Cannabigerol; Akt: Protein Kinase B; mTOR: Mammalian target
of rapamycin; TACE/ADAM17: Tumor necrosis factor-alpha-converting enzyme; ERK: Extracellular-signal-regulated kinase; HIF-1α: Hypoxia-inducible fac-
tor 1 alpha; ROS: Reactive oxygen species; AR: Androgen receptor; CB: Cannabinoid; PSA: Prostate-specific antigen; TRPM8: Transient receptor potential
melastatin 8; p8: Candidate of metastasis 1; ATF-4: Activating transcription factor 4; TRIB3: Tribbles homolog 3
Barbara Dariš, et al.: Cannabinoids and cancer
6
of THC into mice induced apoptosis in T cells and dendritic
cells, leading to immunosuppression. Several studies sug-
gested that cannabinoids are able to suppress inflammatory
responses by downregulating cytokine and chemokine pro-
duction and upregulating T-regulatory cells. Similar results
were obtained with endocannabinoids, i.e.,the administration
of these compounds or the use of inhibitors of enzymes that
break down endocannabinoids had an immunosuppressive
effect and resulted in the recovery from immune-mediated
injury to organs, e.g., in the liver []. As indicated in pre-
vious paragraphs, cannabinoids were able to stimulate cell
proliferation in in vitro and/or in vivo models of several types
of cancer. For example, a treatment with THC in the mouse
mammary carcinoma T expressing low levels of CB and
CB led to enhanced growth of tumor and metastasis, due
to the inhibition of the antitumor immune response, primar-
ily via CB. Moreover, THC led to an increased production
of IL- and IL- in these mice, indicating that it suppresses
the  response by enhancing -associated cytokines as
confirmed by their microarray data (-related genes were
upregulated and -related genes downregulated). Lastly,
the injection of anti-IL- and anti-IL- monoclonal anti-
bodies partially reversed the THC-induced suppression of
the immune response []. In another study, THC promoted
tumorigenicity in two weakly immunogenic murine lung can-
cer models by inhibiting their antitumor immunity; namely,
the inhibitory cytokines IL- and transforming growth factor
beta (TGF-β) were upregulated, while interferon gamma (IFN-
γ) was downregulated at the tumor site and in the spleens of
the mice treated with THC []. ese findings suggest that
THC could decrease tumor immunogenicity and promote
tumor growth by inhibiting antitumor immunity, probably
via CB receptor-mediated, cytokine-dependent pathway.
Additional studies on the interactions between cannabinoids
and immune cells will provide crucial data to improve the effi-
cacy and safety of cannabinoid therapy in oncology [].
SYNTHETIC CANNABINOIDS WITH
POTENTIAL ANTITUMOR EFFECTS
Most synthetic cannabinoids, including dronabinol, nabi-
lone, and synthetic CBD are CB and CB receptor ligands [].
Studies in cells and animals show that they produce similar
qualitative physiological, psychoactive, analgesic, anti-inflam-
matory, and anticancer effects to plant-derived cannabinoids,
but they can be up to × more potent than THC [,].
Similar to naturally occurring cannabinoids, synthetic canna-
binoid agonists also demonstrated anticancer effects in certain
cancer cell lines in vitro [,]. Oil and alcohol-based drops or
capsules of dronabinol and nabilone (synthetic THC) as well
as synthetic CBD are approved to treat cytostatic-induced
nausea/vomiting in cancer patients and to stimulate appetite
in patients with acquired immune deficiency syndrome [].
Recently, a subclass of compounds emerged that act on
metabolic enzymes involved in the regulation of ECS activity,
such as inhibitors of FAAH which increase the levels of endog-
enous cannabinoid AEA. ey were developed with the pur-
pose to treat a variety of neurological diseases, chronic pain,
obesity, and cancer []. Astudy investigating the combination
of the synthetic analogue of AEA Met-F-AEA and the selective
irreversible carbamate-based FAAH inhibitor URB showed
that they synergistically inhibited epidermal growth factor
(EGF)-induced proliferative and chemotactic activity of non-
small cell lung cancer cell lines A and H []. Moreover,
the two FAAH inhibitors URB and arachidonoyl serotonin
(AA-HT) had antimetastatic effects on A lung cancer cell
metastasis []. However, recently in France, the first-in-human
phase I clinical trial of an experimental FAAH inhibitor BIA
-, for neuropathic pain treatment, ended up tragically;
one person died and other four had irreversible brain damage
[,]. e magnetic resonance imaging (MRI) showed evi-
dence of deep cerebral hemorrhage and necrosis in the affected
patients []. Other clinical trials conducted on FAAH inhibi-
tors are Merck’s MK-, Pfizer’s PF-, and Vernalis’
V; no adverse effects were reported with these agents
and they were considered safe in humans [,,]. us, it
could be speculated that the negative effects of BIA -
occurred because the drug may have interacted with a wrong
and unexpected molecular target []. Nevertheless, no FAAH
inhibitor is yet approved for therapeutic use.
To summarize, the antitumor effects of synthetic canna-
binoids such as the inhibition of cell growth, viability, prolif-
eration and invasion, enhanced apoptosis, and suppression of
specific proinflammatory cytokines are generally similar to the
antitumor effects of plant-derived cannabinoids. Moreover,
synthetic cannabinoids have the potential to be even more
selective and potent than their natural counterparts and, thus,
represent a promising therapeutic approach [,].
INTERNATIONAL AND NATIONAL
LEGAL BASIS FOR THE USE OF
CANNABINOIDS
As the number of studies investigating the medical and
therapeutic potential of cannabinoids has increased in recent
years, it is necessary to change the legislation on the use, cul-
tivation, and marketing of cannabinoids. is should, how-
ever, be done with extreme care. In the Republic of Slovenia,
the legislator made a significant progress in this area in ,
which will be elaborated below.
In the EU Member States, the basis for developing and
passing the legislation on cannabinoid use is provided by
7
Barbara Dariš, et al.: Cannabinoids and cancer
international conventions, including: i) the United Nations
Single Convention on Narcotic Drugs,  [] and the 
Protocol amending the Single Convention on Narcotic Drugs,
ii) the Convention on Psychotropic Substances  [], and
iii) the United Nations Convention against Illicit Traffic in
Narcotic Drugs and Psychotropic Substances  [].
e United Nations Convention against Illicit Traffic
in Narcotic Drugs and Psychotropic Substances provides
additional legal mechanisms for enforcing the  Single
Convention on Narcotic Drugs and the  Convention on
Psychotropic Substances. Much of the treaty is devoted to
fighting organized crime, but it also prohibits possession of
drugs for personal use saying that “Subject to its constitutional
principles and the basic concepts of its legal system, each Party
shall adopt such measures as may be necessary to establish as
a criminal offence under its domestic law, when committed
intentionally, the possession, purchase or cultivation of nar-
cotic drugs or psychotropic substances for personal consump-
tion contrary to the provisions of the Conventions”, and this
includes the cultivation of opium poppy, coca bush and can-
nabis plant for the production of narcotic drugs [].
e United Nations Single Convention on Narcotic
Drugs,  sets out four Schedules. Substances controlled
by the state are set out in Schedule I and Schedule II, prepa-
rations in Schedule III, whereas Schedule IV defines drugs,
such as heroin. e Single Conventions Schedules range from
most restrictive to least restrictive, as follows: Schedule IV,
Schedule I, Schedule II, Schedule III. Cannabis, cannabis resin,
extracts and tinctures are included in the Schedule IV of e
Single Convention on Narcotic Drugs. Tetrahydrocannabinol
(THC, synonym delta--THC) is included in the Schedule I
of the Convention on Psychotropic Substances. Delta--THC
and its stereoisomers, including dronabinol, are listed in the
Addendum  to the Convention on Psychotropic Substances.
Nabilone is not controlled under international law [].
Under the EU regulatory framework, the subject mat-
ter is regulated by Directive //EC of the European
Parliament and of the Council of November  on the
Community code relating to medicinal products for human
use []. Pursuant to the Article  of Directive //EC, this
Directive shall not apply to medicinal products prepared in a
pharmacy in accordance with a medical prescription, medic-
inal products prepared in a pharmacy in accordance with the
prescriptions of a pharmacopoeia, and medicinal products
intended for research and development trials. is Directive
also allowed the use of medicinal products for human use,
intended to be placed on the market in the Member States
and either prepared industrially or manufactured by a method
involving an industrial process. is made cannabinoid-based
medicinal products available in all the Member States, pro-
vided they are permitted by the national legislation [].
In the Republic of Slovenia, illicit drugs including cannabis,
are governed by the following regulations: i) Production of and
Trade in Illicit Drugs Act [], ii) Act Regulating the Prevention
of the Use of Illicit Drugs and the Treatment of Drug Users [],
iii) Criminal Code of the Republic of Slovenia[], iv) Decree
on the classification of illicit drugs [], v) Rules on method and
form of record-keeping and of reports on illicit drugs [], and
vi) the Rules governing the procedures for the issue of licenses
for illicit drugs marketing [].
As previously mentioned, in  the adoption of the
Decree amending the Decree on the classification of illicit
drugs [] was made. is Decree removed cannabis from
Schedule I and placed it under Schedule II, with the note
that the use of cannabis for medicinal purposes is permit-
ted in accordance with the Medicinal Products Act [] and
Pharmacy Services Act [], and in accordance with the
rules and regulations governing the prescribing of cannabi-
noid-based drugs.
e aforementioned amendment to the Decree on the
classification of illicit drugs now allows patients to use medic-
inal cannabis as a means of treatment, including the canna-
bis plant and cannabis resin. Medicinal products are thus not
limited anymore to products containing nabilone or cannabis
extracts, but also extend to tinctures adjusted and harmonized
to delta--THC, as long as they meet the conditions laid down
in the Medicinal Products Act.
Changes in the legislation on the use of cannabinoids for
medical purposes and inclusion of these compounds in the
list of medicinal products needs to be coordinated with the
changes in both labor law and the regulation of workplace
drug testing. Naturally, any change should be adopted in
strict agreement with work, health, and safety regulations and
ensure smooth workflow for the employees.
CONCLUSION
Cannabinoids are a large and important class of complex
compounds that have a promising therapeutic potential for
the treatment of variety of diseases, including cancer. In this
review, we focused on studies that provided evidence for anti-
cancer effects of plant-derived and synthetic cannabinoids
and their potential mechanisms of action. Cannabinoids
were able to effectively modulate tumor growth in different
in vitro and in vivo cancer models, however, these anticancer
effects appears to be dependent on cancer type and drug dose.
Understanding how cannabinoids are able to modulate essen-
tial cellular processes involved in tumorigenesis, such as the
progression through the cell cycle, cell proliferation and cell
death, as well as the interactions between cannabinoids and
immune system are crucial for improving existing medica-
tions and developing new therapeutic approaches.
Barbara Dariš, et al.: Cannabinoids and cancer
8
Although still strict, the legislation on the use of canna-
bis-based medications has been improved, especially fol-
lowing the promising results of related basic research. e
Republic of Slovenia established a legal basis for the use of
cannabinoids in the years  and . e increasing popu-
larity of cannabis and cannabis-based medication should lead
to clear regulatory guidelines on their use, in the near future.
ACKNOWLEDGMENTS
e authors acknowledge Jan Schmidt for his initial help in
preparing this manuscript.
DECLARATION OF INTERESTS
e authors declare no conflict of interests.
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... 9 No entanto, estudos apontam que o sistema endocanabinóide pode oferecer o potencial para controlar outros aspectos da doença. 10 Embora haja evidências limitadas de que os canabinoides da cannabis estão tendo atividades imunossupressoras 9-10 significativas que influenciarão a autoimunidade recorrente, há evidencias que eles podem limitar a neuro degeneração que leva à incapacidade progressiva. 11 O Mal de Parkinson (MP) é uma condição degenerativa que afeta a neurotransmissão dopaminérgica nos gânglios da base, resultando em hipocinesia. ...
... 12 Nesse contexto, os compostos bioativos da Cannabis sativa têm demonstrado efeitos antioxidantes, anti-inflamatórios e neuroprotetores em modelos pré-clínicos de doenças do sistema nervoso central. 13 No entanto, a maioria dos estudos que comprovam a capacidade dos canabinoides em retardar a progressão da doença e prolongar a sobrevida na (EM) 8,[9][10][11] foi realizada em modelo animal, enquanto os poucos ensaios clínicos que investigaram medicamentos à base de canabinoides se concentraram apenas no alívio dos sintomas relacionados a (EM), 8 não no controle da progressão da doença. 10 Embora os canabinoides possam ter benefícios clínicos potenciais, seu uso não é isento de possíveis efeitos adversos e mais pesquisas são necessárias para definir seu papel na prática médica. ...
... 13 No entanto, a maioria dos estudos que comprovam a capacidade dos canabinoides em retardar a progressão da doença e prolongar a sobrevida na (EM) 8,[9][10][11] foi realizada em modelo animal, enquanto os poucos ensaios clínicos que investigaram medicamentos à base de canabinoides se concentraram apenas no alívio dos sintomas relacionados a (EM), 8 não no controle da progressão da doença. 10 Embora os canabinoides possam ter benefícios clínicos potenciais, seu uso não é isento de possíveis efeitos adversos e mais pesquisas são necessárias para definir seu papel na prática médica. 5,[9][10] Estudos indicam que (CBD) pode ter potencial terapêutico no tratamento de distúrbios neurológicos (por exemplo, doença de Huntington, doença de Parkinson e esclerose múltipla) 7 e doença inflamatória do intestino, bem como ter atividade antibacteriana. ...
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Objetivo: apresentar o estado da arte das publicações expressas na literatura cientifica mundial sobre a temática, bem comoidentificar os benefícios terapêuticos da Cannabis medicinal no tratamento dos sintomas das doenças neurodegenerativasespecificamente doenças de Parkinson, esclerose múltipla e Alzheimer. Método: trata-se de uma revisão integrativa da literatura,cuja busca de dados foi realizada nas bibliotecas virtuais. Web of Science, Scopus, Medline, Lilacs, Cochrane Library e Scielo noperíodo de agosto a outubro de 2021. Resultados: foram encontrados 158 artigos. Vinte e tres artigos foram selecionadospara serem lidos na íntegra e 8 atenderam aos critérios desta revisão. Conclusão: as evidências mostram que embora cada vezmais prescritos ou autorizados, a cannabis medicinal ou os Canabinóides para a doenças neurodegenerativas continuam a sercontroversos para muitos médicos
... De acordo com a International Association for the Study of Pain, (IASP), 10 a dor é sempre subjetiva e pessoal. 10 Dados com Instituto Nacional de Câncer (INCA) 5 a incidência de dor moderada ou intensa ocorrem em 30% dos pacientes com câncer recebendo tratamento e em 60% a 90% dos pacientes com câncer avançado. 11 As estimativas de prevalência de dor crônica provavelmente variam dependendo da amostra da população pesquisada e do método de avaliação. ...
... 11 As estimativas de prevalência de dor crônica provavelmente variam dependendo da amostra da população pesquisada e do método de avaliação. [10][11] As terapias para o tratamento da dor crônica incluem vários agentes farmacológicos 12 como: antidepressivos tricíclicos, inibidores da recaptação da serotonina--norepinefrina e analgésicos opioides 11 . No entanto, esses medicamentos oferecem alívio limitado da dor e estão associados a efeitos adversos. ...
... [11][12] Embora os canabinoides possam ter benefícios clínicos potenciais, seu uso não é isento de possíveis efeitos adversos e mais pesquisas são necessárias para definir seu papel na prática médica. 5,[9][10] O objetivo deste estudo é apresentar o estado da arte das publicações expressas na literatura cientifica mundial sobre a temática, bem como identificar os benefícios terapêuticos da Cannabis medicinal no tratamento da dor. ...
Article
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Objetivo: apresentar o estado da arte das publicações expressas na literatura cientifica mundial sobre a temática, bem como identificar os benefícios terapêuticos da Cannabis medicinal no tratamento da dor. Método: trata-se de uma revisão integrativa da literatura, cuja busca de dados foi realizada nas bibliotecas virtuais. Web of Science, Scopus, Medline, IBECS, Lilacs, Cochrane Library, Emerald Insight e Scielo no período de agosto a outubro de 2021. Resultados: foram encontrados 367 artigos. Quarenta e três artigos foram selecionados para serem lidos na íntegra e 15 atenderam aos critérios desta revisão. Conclusão: as evidências mostram que embora cada vez mais prescritos ou autorizados, a cannabis medicinal ou os Canabinóides para a dor crónica continuam a ser controversos para muitos médicos.
... However, the mortality rate is still high and many patients are suffering from the side effects of treatment (4). In addition, pancreatic cancer is usually resistant to the most available chemotherapy drugs (5), making new drugs development more interested. ...
... For instance, cannabinoids can reduce tumor progression by inducing apoptosis and inhibiting the proliferation of tumor cells (9). The role of cannabinoids as antitumor drugs has been reported in patients with pancreatic cancer due to cannabinoid receptors are expressed in pancreatic cells and upregulated in pancreatic cancer cells (5). Furthermore, cannabis extract has been reported to be used as a therapeutic agent in drug-resistance cancer (10). ...
... Several studies reported chemoresistance in pancreatic cancer including 5-FU chemotherapy (25,27,46,47). However, the previous studies reported that the use of cannabinoids in combination with chemotherapy showed synergistic effects and cannabinoids attenuated side effects of chemotherapy (48,49) and increase survival in transgenic pancreatic cancer animal models (5). The current study demonstrates that 5-FU can prevent tumor cell proliferation and cannabinoids can induce apoptosis of tumor cells. ...
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Background Pancreatic cancer is considered a rare type of cancer, but the mortality rate is high. Cannabinoids extracted from the cannabis plant have been interested as an alternative treatment in cancer patients. Only a few studies are available on the antitumor effects of cannabinoids in pancreatic cancer. Therefore, this study aims to evaluate the antitumor effects of cannabinoids in pancreatic cancer xenografted mouse model. Materials and Methods Twenty-five nude mice were subcutaneously transplanted with a human pancreatic ductal adenocarcinoma cell line (Capan-2). All mice were randomly assigned into 5 groups including negative control (gavage with sesame oil), positive control (5 mg/kg 5-fluorouracil intraperitoneal administration), and cannabinoids groups that daily received THC:CBD, 1:6 at 1, 5, or 10 mg/kg body weight for 30 days, respectively. Xenograft tumors and internal organs were collected for histopathological examination and immunohistochemistry. Results The average tumor volume was increased in all groups with no significant difference. The average apoptotic cells and caspase-3 positive cells were significantly increased in cannabinoid groups compared with the negative control group. The expression score of proliferating cell nuclear antigen in positive control and cannabinoids groups was decreased compared with the negative control group. Conclusions Cannabinoids have an antitumor effect on the Capan-2-derived xenograft mouse model though induce apoptosis and inhibit proliferation of tumor cells in a dose-dependent manner.
... Aunque hasta la fecha el uso de cannabinoides en el cáncer se limita a aliviar síntomas como las náuseas o el dolor, en algunos estudios se han explorado sus propiedades antitumorales (14). El papel del sistema endocannabinoide no está completamente claro en el cáncer, sin embargo, se ha sugerido que los receptores de cannabinoides y los ligandos endógenos se sobreexpresan en el tejido tumoral (14). ...
... Aunque hasta la fecha el uso de cannabinoides en el cáncer se limita a aliviar síntomas como las náuseas o el dolor, en algunos estudios se han explorado sus propiedades antitumorales (14). El papel del sistema endocannabinoide no está completamente claro en el cáncer, sin embargo, se ha sugerido que los receptores de cannabinoides y los ligandos endógenos se sobreexpresan en el tejido tumoral (14). Se ha descubierto que los cannabinoides inhiben la proliferación de células tumorales, la angiogénesis, la invasión tumoral e inducen la apoptosis in vitro e in vivo mediante la activación de los receptores cannabinoides. ...
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Since ancient times cannabis has been used for recreational and medicinal purposes. It is a significant source of chemical compounds, most of them called phytocannabinoids. These compounds have several physiological effects and produce their effects primarily by binding to endogenous cannabinoid receptors such as CB1 and CB2, among others. Cannabis has potential therapeutic properties and its preparations have been used as traditional remedies to treat pain and emesis. Synthetic cannabinoids are used clinically as analgesics, antispastics, antiemetics, and appetite stimulants. Significant cannabis toxicity is rare in adults; however, it can produce countless acute and chronic side effects. The quality of the evidence in this field is limited by the short duration of the trials, poor sample sizes, lack of a control group, and the existence of bias in most of the reviewed studies. Therefore, a larger number of studies with better methodological quality is required to support the safe use of this therapy. The decision to include cannabinoids as a treatment for any of the conditions described will depend on the evidence, the use of previous therapies, and the type of patient.
... 10 In patients with cancer, cannabinoids have mainly been used as part of palliative care to alleviate pain, relieve nausea and stimulate appetite. 11 Thailand legalized medical cannabis in February 2019, becoming the first country in Southeast Asia to regulate medical treatment. 12 Currently, there are two treatment options for palliative cancer patients in Thailand; the standard current treatment and the new cannabis treatment. ...
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Background : Cholangiocarcinoma (CCA) incidence in Northeastern Thailand is very high and a major cause of mortality. CCA patients typically have a poor prognosis and short-term survival rate due to late-stage diagnosis. Thailand is the first Southeast Asian country to approve medicinal cannabis treatment, especially for palliative care with advanced cancer patients. Methods : A retrospective cohort comparative study of survival rates among 491 newly diagnosed advanced CCA patients was carried out between September 1, 2019, and June 30, 2021. A total of 404 patients were in the standard palliative care pain management treatment group (ST), and 87 were in the medicinal cannabis treatment group (CT). Patients with CCA were recruited from four tertiary hospitals and two secondary hospitals in five provinces of Northeast Thailand. The cumulative survival rates were calculated by the Kaplan-Meier method, and independent prognostic factors were investigated using Cox regression. Results : For ST patients, there was a total follow-up time of 790 person-months, with a mortality rate of 48.35/100 person-months. For CT patients the total follow-up time was 476 person-months, with mortality rate of 10.9/ 100 person-months. The median survival time after registration at a palliative clinic was 0.83 months (95% CI: 0.71–0.95) for ST and 5.66 months (95% CI: 1.94–9.38) for CT. Multivariate analysis showed that CT treatment protocol was associated with a significantly better survival (P value <0.001; median time of CT, 5.66 months (95% CI: 1.94–9.38); median time of ST, 0.83 months (95% CI: 0.71–0.95). Therefore, CT had a reduced probability of dying from the disease (HR adj ., 0.28 (95% CI: 0.20–0.37) Conclusions : The medical cannabis increased overall survival rates among CCA patients.
... Cannabinoids can effectively modulate tumor growth, both in vitro and in vivo cancer models, however, the anticancer effects seem to be dependent on the type of cancer and drug dose. Understanding how cannabinoids can modulate essential cellular processes involved in tumorigenesis (progression through the cell cycle, cell proliferation and cell death) and the interactions between cannabinoids and the immune system are crucial for improving existing medications and developing new therapeutic approaches [79]. Cannabinoids are particularly successful at suppressing the pain symptoms of chemotherapy-induced and other peripheral neuropathies, but their broad usage is constrained by central nervous system (CNS)mediated adverse effects. ...
Article
Patients diagnosed with cancer often experience pain during their treatment course, making it difficult to care for themselves and continue with their activities of daily living. When cancer is found at later stages, the pain can become severe and constant; reducing their quality of life and significantly affecting mental and physical well-being. Despite opioids being known to provide adequate analgesia for higher pain levels, they are often the reason for under-dosing because of their adverse effects and concern for addiction. There are also patients who do not respond well to opioids because of genetic anomalies or personal preference. Therefore, there is a need for novel non-opioid cancer pain treatments. There are many new cancer pain treatments that are emerging. This manuscript discusses cancer pain, risk factors, epidemiology, guidelines for the treatment of cancer pain, personalization of cancer pain therapy, breakthrough pain, cancer-induced peripheral neuropathy, established cancer pain treatment options, and novel emerging cancer pain treatment options.
Chapter
Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors. Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades. In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use.
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Cannabis is one of the most popular drugs on the one side and a medicinal product on the other. It contains about 70 different psychoactive compounds, whose function is still not fully undrestood. International legal framework in the field of illicit drugs is defined by three United Nations Conventions, namely the Single Convention on Narcotic Drugs, 1961, amended in 1972, the Convention on Psychotropic Substances, 1971 and the Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988. The European Union Member States classify drugs and precursors in accordance with these three conventions. Within the framework of their national laws, the Member States regulate the scope of illicit drugs in different ways in detail, thereby enabling their medical use and preventing their potential abuse at the same time. In Slovenia, recently amended Regulation on the classification of illicit drugs enables the availability of medicines with isolated or synthesized 9-tetrahydrocannabinol, nabilone, and medicines with extracts from cannabis, including tinctures, standardized to delta-9-tetrahydrocannabinol. Based on this regulation pharmacists can also compound magistral and galenic medicines from those substances.
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The cannabinoid receptors 1 and 2 (CNR1&2) are overexpressed in a variety of malignant diseases and cannabinoids can have noteworthy impact on tumor cell viability and tumor growth. Patients diagnosed with chronic lymphocytic leukemia (CLL) present with very heterogeneous disease characteristics translating into highly differential risk properties. To meet the urgent need for refinement in risk stratification at diagnosis and the search for novel therapies we studied CNR expression and response to cannabinoid treatment in CLL. Expression levels of CNR1&2 were determined in 107 CLL patients by real-time PCR and analyzed with regard to prognostic markers and survival. Cell viability of primary CLL cells was determined in suspension and co-culture after incubation in increasing cannabinoid concentrations under normal and reduced serum conditions and in combination with fludarabine. Impact of cannabinoids on migration of CLL cells towards CXCL12 was determined in transwell plates. We found CNR1&2 to be overexpressed in CLL compared to healthy B-cells. Discriminating between high and low expressing subgroups, only high CNR1 expression was associated with two established high risk markers and conferred significantly shorter overall and treatment free survival. Viability of CLL primary cells was reduced in a dose dependent fashion upon incubation with cannabinoids, however, healthy cells were similarly affected. Under serum reduced conditions, no significant differences were observed within suspension and co-culture, respectively, however, the feeder layer contributed significantly to the survival of CLL cells compared to suspension culture conditions. No significant differences were observed when treating CLL cells with cannabinoids in combination with fludarabine. Interestingly, biologic activity of cannabinoids was independent of both CNR1&2 expression. Finally, we did not observe an inhibition of CXCL12-induced migration by cannabinoids. In contrast to other tumor entities, our data suggest a limited usability of cannabinoids for CLL therapy. Nonetheless, we could define CNR1 mRNA expression as novel prognostic marker.
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Vanilloids including capsaicin and resiniferatoxin are potent transient receptor potential vanilloid type 1 (TRPV1) agonists. TRPV1 overstimulation selectively ablates capsaicin-sensitive sensory neurons in animal models in vivo. The cytotoxic mechanisms are based on strong Na+ and Ca2 + influx via TRPV1 channels, which leads to mitochondrial Ca2 + accumulation and necrotic cell swelling. Increased TRPV1 expression levels are also observed in breast and prostate cancer and derived cell lines. Here, we examined whether potent agonist-induced overstimulation mediated by TRPV1 might represent a means for the eradication of prostate carcinoma (PC-3, Du 145, LNCaP) and breast cancer (MCF7, MDA-MB-231, BT-474) cells in vitro. While rat sensory neurons were highly vanilloid-sensitive, normal rat prostate epithelial cells were resistant in vivo. We found TRPV1 to be expressed in all cancer cell lines at mRNA and protein levels, yet protein expression levels were significantly lower compared to sensory neurons. Treatment of all human carcinoma cell lines with capsaicin didn't lead to overstimulation cytotoxicity in vitro. We assume that the low vanilloid-sensitivity of prostate and breast cancer cells is associated with low expression levels of TRPV1, since ectopic TRPV1 expression rendered them susceptible to the cytotoxic effect of vanilloids evidenced by plateau-type Ca2 + signals, mitochondrial Ca2 + accumulation and Na+- and Ca2 +-dependent membrane disorganization. Moreover, long-term monitoring revealed that merely the ectopic expression of TRPV1 stopped cell proliferation and often induced apoptotic processes via strong activation of caspase-3 activity. Our results indicate that specific targeting of TRPV1 function remains a putative strategy for cancer treatment.