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Towards the Use of Cannabinoids as Anti Cancer Agents - Guzman

Towards the Use of Cannabinoids as Anti Cancer Agents - Guzman

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 Acknowledgements
The author apologizes to those authors whose work could notbe cited directly owing to space constraints. For stimulatingdiscussions and critical reading of the manuscript the authoris very grateful to S. Brabletz and M. Swierk. T.B. is supportedby the DFG (no. BR 1399/6-1 and the SFB 850, B2), theDeutsche Krebshilfe (grant no. 109430), the SpemanGraduate School of Biology and Medicine (SGBM) and theBIOSS Centre for Biological Signalling Studies.
Competing interests statement
The author declares no competing financial interests.
FURTHER INFORMATION
Thomas Brabletz’s homepage: 
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
Few plant species have been the subject of somuch scientific, clinical and social debate as
Cannabis sativa
L. (marijuana). Preparationsfrom this plant have been used for many centuries both medicinally and recreation-ally. However, the chemical structures of their unique active components — the can-nabinoids — were not elucidated until the1960s. Three decades later, the first solidclues on cannabinoid molecular actionwere established, which led to an impressiveexpansion of basic cannabinoid research andto a renaissance in the study of the thera-peutic effects of cannabinoids in variousfields, including oncology.Today, it is widely accepted that, of the~70 cannabinoids produced by 
C. sativa
,Δ
9
-tetrahydrocannabinol (THC) is the mostrelevant owing to its high potency and abun-dance in plant preparations
1,2
. THC exerts awide variety of biological effects by mimick-ing endogenous substances — the so-calledendocannabinoids (the two most studiedbeing anandamide
3
and 2-arachidonoyl-glycerol (2-AG)
4,5
) — that engage specificcell-surface cannabinoid receptors
6
 
(FIG. 1)
.So far, two major cannabinoid-specificreceptors — CB1
 
and CB2 — have beencloned and characterized from mamma-lian tissues
7,8
. In addition, other receptors,including the transient receptor potentialcation channel subfamily V member 1(TRPV1) and certain orphan G protein-coupled receptors, GPR55, GPR119 andGPR18, have been proposed to act as endo-cannabinoid receptors
6
. Most of the effectsthat are produced by cannabinoids in thenervous system and in non-neural tissuesrely on CB1 receptor activation. Expressionof this receptor is abundant in the centralnervous system, particularly in discrete areasthat are involved in the control of motorbehaviour (such as the basal ganglia and cer-ebellum), memory and learning (the cortexand hippocampus), emotions (the amyg-dala), sensory perception (the thalamus),and autonomic and endocrine functions(the hypothalamus, pons and medulla). Inaddition, CB1 receptors are expressed inperipheral nerve terminals and in many extra-neural sites. By contrast, the CB2receptor was initially described as presentin the immune system
6
, but more recently it has also been shown to be expressed inadditional cell types
9,10
. Notably, expressionof CB1 and CB2 receptors has been foundin many types of cancer cells, althoughthis does not necessarily correlate with theexpression of these receptors in the tissuetype of origin
9,11,12
.The endocannabinoids, together with theirreceptors and the proteins that are responsiblefor their synthesis, transport and degradation,constitute the endocannabinoid system. Asidefrom its pivotal neuromodulatory activity 
13
 
(FIG. 1)
, the endocannabinoid system exertsother regulatory functions in the body, suchas the control of cardiovascular tone, energy metabolism, immunity and reproduc-tion
14,15
. This miscellaneous activity makesthe pharmacological manipulation of theendocannabinoid system a promising strat-egy for the management of many differentdiseases. Specifically, cannabinoids are well-known to exert palliative effects in cancerpatients
14,15
, and their best-established use isin the inhibition of chemotherapy-inducednausea and vomiting
15,16
. Today, capsules of THC, named dronabinol (Marinol; Solvay Pharmaceuticals), and its synthetic analogue
OPINION
Towards the use of cannabinoidsas antitumour agents
Guillermo Velasco, Cristina Sánchez and Manuel Guzmán
Abstract | Various reports have shown that cannabinoids (the active componentsof marijuana and their derivatives) can reduce tumour growth and progression inanimal models of cancer, in addition to their well-known palliative effects on somecancer-associated symptoms. This Opinion article discusses our currentunderstanding of cannabinoids as antitumour agents, focusing on recent insightsinto the molecular mechanisms of action, including emerging resistancemechanisms and opportunities for combination therapy approaches. Such
knowledge is required for the optimization of preclinical cannabinoid-based
therapies and for the preliminary clinical testing that is currently underway.
PERSPECTIVES
 436
|
JUNE 2012
|
VOLUME 12
www.nature.com/reviews/cancer
© 2012 Macmillan Publishers Limited. All rights reserved
 
 
OOH
THC
OOOOHOHNHO
Plant-derived cannabinoidEndogenous cannabinoids
PostsynapticneuronPresynapticneuronNeurotransmittersCB1
Ca
2+
Activity(for example,
Ca
2+
 concentration)PrecursorAEA or2-AGReceptor2-AGAEA
H
nabilone (Cesamet; Meda Pharmaceuticals),are approved for this purpose. Cannabinoidsalso inhibit pain, and thus a standardizedcannabis extract, nabiximols (Sativex; GWPharmaceuticals) has been approved inCanada and is currently the subject of large-scale Phase III clinical trials for managingcancer-associated pain. Another potentialpalliative effect of cannabinoids in oncol-ogy, which is supported by Phase III clinicaltrials, includes appetite stimulation andattenuation of wasting. In relation to this,dronabinol can currently be prescribed foranorexia that is associated with weight lossin patients with AIDS.The therapeutic potential of cannabinoidsin oncology might not be restricted to theiraforementioned palliative actions. Thus,numerous studies carried out during the pastfew years have provided evidence showingthat THC and other cannabinoids exhibitantitumour effects on a wide range of animalmodels of cancer
12,16
(Supplementary infor-mation S1(table)). Moreover, these observa-tions led to the development of a pilot clinicalstudy to investigate the antitumour activity of THC in patients with glioma. Nonetheless,a few studies have shown that, under cer-tain conditions, cannabinoid treatment canstimulate cancer cell proliferation
in vitro
17,18
 and can interfere with the tumour-suppressorrole of the immune system
19,20
. Likewise,there have been conflicting reports regardingthe role (tumour suppressor or oncogenic)of the endocannabinoid system in cancer
21
.In this Opinion article we summarizethese observations and provide an integrated view of the molecular mechanisms that areresponsible for cannabinoid anti-tumouractivity. Likewise, we discuss the experimen-tal evidence that supports the existence of mechanisms of resistance to the cell death-promoting actions of THC in certain types of cancer cells, as well as the possible strategiesthat could be undertaken to overcome suchresistance. We also discuss the preclinicaldata that support the potential combinedadministration of cannabinoids and otherdrugs in anticancer therapies.
The endocannabinoid system and cancer
Little is currently known about the biologi-cal role of the endocannabinoid system incancer physiopathology. Although thereare some exceptions that may be tumourtype-specific, both cannabinoid receptorsand their endogenous ligands are generally upregulated in tumour tissue compared withnon-tumour tissue
16,21–23
. Additionally, dif-ferent studies have associated the expressionlevels of cannabinoid receptors, endocan-nabioids and endocannabinoid-metabolizingenzymes with tumour aggressiveness
21,24,25
,which suggests that the endocannabinoidsystem may be over-activated in cancer andso it may be pro-tumorigenic
21
. In supportof this, in mouse models of cancer, geneticablation of CB1 and CB2 receptors reducesultraviolet light-induced skin carcinogen-esis
26
, and CB2 receptor overexpressionenhances predisposition to leukaemiafollowing leukaemia virus infection
27
.Conversely, and in line with evidence thatthe pharmacological activation of cannabi-noid receptors reduces tumour growth
12,16
, theupregulation of endocannabinoid-degradingenzymes has been observed in aggressivehuman tumours and cancer cell lines
24,25
,indicating that endocannabinoid signallingcan also have a tumour-suppressive role. Insupport of this, the deletion of CB1 recep-tors accelerates intestinal tumour growth ina genetic mouse model of colon cancer
28
;increased endocannabinoid levels diminishazoxymethane-induced precancerous lesionsin the mouse colon
29
; and a reduction in theexpression of the endocannabinoid-degradingenzyme monoacylglycerol lipase reducestumour growth in xenografted mice
24
.Therefore, further studies — includingthose involving the genetic or pharmaco-logical manipulation of the endocannabi-noid system — will be required to dissect theprecise signalling mechanisms that regulatecannabinoid-induced cell death or cellproliferation. Such information is neededto clarify the contextual determinants thatdetermine when this system acts as a guard-ian, or, alternatively, as an inducer of tumorigenesis or tumour progression.
Preclinical antitumour activity
Since the late 1990s, a large body of evi-dence has accumulated demonstrating that various cannabinoids exert antitumoureffects in a wide variety of experimentalmodels of cancer, ranging from cancer celllines in culture to genetically engineeredmice (Supplementary information S1(table)). Multiple cannabinoids have shownthis activity, including THC; the endocan-nabinoids 2-AG and anandamide; anddifferent synthetic cannabinoid receptoragonists that have either comparable affin-ity for CB1 and CB2 receptors (for example,WIN 55,212-2 and HU-210), higher affinity for CB1 (for example, methanandamide)or higher affinity for CB2 (for example,JWH-133). These findings strongly support
Figure 1 |
Cannabinoids and endocannabinoids.
Plant-derived cannabinoids such as
Δ
9
-tetrahydrocannabinol (THC) function in the body by activating specific cannabinoid receptors thatare normally engaged by a family of endogenous ligands — the endocannabinoids anandamide(
N
-arachidonoylethanolamine (AEA))
3
and 2-arachidonoylglycerol (2-AG)
4,5
. A well-established function of the endocannabinoid system is its role in neuromodulation. After the binding of 
neurotransmitters to their receptors, activated postsynaptic neurons synthesize membrane-bound
endocannabinoid precursors and cleave them to release endocannabinoids
13
. This is generally inducedby an increase in the cytosolic concentration of free Ca
2+
 
(REF. 13)
. Endocannabinoids subsequently actas retrograde messengers by binding to presynaptic CB1 cannabinoid receptors, which are coupled tothe inhibition of Ca
2+
influx into the cell and, in turn, to the blockade of neuro transmitter release
13
. Thisallows the tuning of key biological processes such as memory, movement, appetite and pain
14
. Figure ismodified, with permission, from REF. 16
©
 
(2003) Macmillan Publishers Ltd. All rights reserved.
PERSPECTIVES
NATURE REVIEWS
|
 
CANCER 
VOLUME 12
|
JUNE 2012
|
 
 437
© 2012 Macmillan Publishers Limited. All rights reserved
 
 
Induction of apoptosis
Inhibition of proliferation
Inhibition of adhesion
Inhibition of migration
Inhibition of invasionCancer cells
VEGF pathway
MMP2 (and modulationof other targets)
ER stress and autophagyCannabinoids
Inhibition of angiogenicsignals Uncontrolledcancer growthMetastaticcapabilitySustainedangiogenesis
the suggestion that, aside from the roleof the endogenous cannabinoid system incancer, pharmacological stimulation of CBreceptors is, in most cases, antitumorigenic.Nonetheless, a few reports have proposeda tumour-promoting effect of cannabi-noids
17–20
. These apparently conflictingobservations are discussed below.Cannabinoids impair tumour progressionat different levels. Their most prevalent effectis the induction of cancer cell death by apop-tosis and the inhibition of cancer cell prolifer-ation
(FIG. 2)
. At least one of these actions hasbeen demonstrated in almost all the cancercell types tested (
TABLE 1
; see Supplementary information S1 (table)). In addition,
in vivo
 experiments have shown that cannabinoidsimpair tumour angiogenesis and block invasion and metastasis
(FIG. 2)
.
Mechanisms of antitumour effects
Induction of cancer cell death.
A consider-able amount of the research that has beenconducted so far on the mechanism of can-nabinoid antitumour activity has focused onglioma cells. Initial studies showed that THCand other cannabinoids induce the apoptoticdeath of glioma cells through CB1- andCB2-dependent stimulation of the
de novo
 synthesis of the pro-apoptotic sphingolipidceramide
23,30–32
.Further studies, based on the analy-sis of the gene expression profiles of THC-sensitive and THC-resistant gliomacells, gave further insight into the specificsignalling events downstream of ceramidethat are activated in cancer cells by cannabi-noids
33
. THC acutely upregulates the expres-sion of the stress-regulated protein p8 (alsoknown as NUPR1), which is a transcrip-tional regulator that has been implicated inthe control of tumorigenesis and tumourprogression
34
, together with several of itsdownstream targets such as the endoplasmicreticulum (ER) stress-related transcriptionfactors ATF4 and CHOP (also known asDDIT3), as well as the pseudokinasetribbles-homologue 3 (TRIB3)
33
 
(FIG. 3)
.The ER stress response is a complexintracellular signalling pathway thatbecomes activated in response to Ca
2+
 depletion, oxidative injury, a high-fat diet,hypoglycaemia, viral infections and expo-sure to certain anticancer agents
35
. ER stressaims to lessen the protein load on the ER by coordinating a temporal shutdown inprotein translation and a complex pro-gramme of gene transcription to increasethe ER protein-folding capacity. If this tran-scriptional programme fails to re-establishproper ER homeostasis, persistence in ER stress can induce cell death, usually by activating intrinsic apoptosis
35
. ER stress, asinduced by different anticancer agents, canalso lead, through different mechanisms
36
,to the stimulation of autophagy, which is anessential cellular process that participates ina number of physiological functions in thecell
36,37
.During autophagy, organelles and othercytoplasmic components are engulfedin double-membrane vesicles that aredesignated autophagosomes. The matura-tion of these vesicles involves their fusionwith lysosomes, which in turn leads to thedegradation of the autophagosome compo-nents by lysosomal enzymes
37
. Autophagy is primarily a cytoprotective mechanism,although its activation can also lead to celldeath
37,38
. Indeed, THC-triggered stimula-tion of the p8-regulated pathway enhancesthe inhibitory interaction of TRIB3 witha pro-survival kinase, AKT, which leadsto the inhibition of the mammalian targetof rapamycin complex 1 (mTORC1) andthe subsequent stimulation of autophagy-mediated cell death
39
 
(FIG. 3)
. Cannabinoidsinduce autophagy in different types of can-cer cells in culture
(TABLE 1)
, and pharmaco-logical or genetic inhibition of autophagy prevents cannabinoid antitumour action indifferent animal models of cancer
(FIG. 3)
,thus demonstrating that autophagy isimportant for cannabinoid antineoplasticactivity 
39,40
. Moreover, autophagy blockadeprevents cannabinoid-induced apoptosisand cell death, whereas apoptosis blockadeprevents cannabinoid-induced cell deathbut not autophagy 
39,40
. This indicates thatautophagy is upstream of apoptosis in themechanism of cannabinoid-induced celldeath
(FIG. 3)
.The direct participation of the p8-mediated autophagy pathway in the anti-tumour action of cannabinoids has beenclearly demonstrated in glioma cells, as wellas in pancreatic and hepatic cancer cells
33,39–41
.At least part of this signalling route has alsobeen found to be upregulated on cannabi-noid treatment in other types of cancer cells
(TABLE 1)
. This suggests that — with some variations — this could be a general mecha-nism by which the activation of CB1 and CB2receptors promotes cancer cell death.Additional mechanisms may nonethelesscooperate with the p8-mediated autophagy pathway to evoke cancer cell death
(FIG. 3)
.For example, in hepatocellular carcinomacells, cannabinoids can trigger an ER stress-dependent activation of AMPK that cooper-ates with the TRIB3-mediated inhibition of the AKT–mTORC1 axis in the stimulationof autophagy-mediated cell death
40
. In mela-noma
42
, breast carcinoma
22
and prostatecarcinoma
43
cells cannabinoids can inducecell cycle arrest together with apoptosis
22,42,43
.Notably, cannabinoid antiproliferative
Figure 2 |
General mechanisms of cannabinoid antitumour action.
Cannabinoids block tumourprogression by targeting several hallmarks of cancer. They impair uncontrolled cancer cell growth byinducing cancer cell death by apoptosis
23,31,39,41
and by inhibiting cancer cell proliferation
22,42,85
. Theyalso hamper tumour angiogenesis by downregulating the vascular endothelial growth factor (VEGF)pathway in cancer cells
30,49–51
. Finally, cannabinoids hinder metastasis by inhibiting cancer cell adhe-sion and migration/invasiveness through the modulation of matrix metalloproteinase 2 (MMP2), tissueinhibitor of matrix metalloproteinases 1 (TIMP1), inhibitor of DNA binding 1 (ID1) and perhaps othertargets
53–57,59
. ER, endoplasmic reticulum.
PERSPECTIVES
 438
|
JUNE 2012
|
VOLUME 12
www.nature.com/reviews/cancer
© 2012 Macmillan Publishers Limited. All rights reserved

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