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Guzman Cancer

Guzman Cancer

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Preparations from
Cannabis sativa 
have been used formany centuries both medicinally and recreationally.However,the chemical structure oftheir unique activecomponents — the
CANNABINOIDS
— was not elucidateduntil the early 1960s.As they are highly hydrophobic,cannabinoids were initially believed to mediate theiractions by inserting directly into biomembranes.Thisscenario changed markedly in the early 1990s,when spe-cific cannabinoid receptors were cloned and theirendogenous ligands were characterized,therefore pro-viding a mechanistic basis for cannabinoid action.Thisled not only to an impressive expansion ofbasiccannabinoid research,but also to a renaissance in thestudy ofthe therapeutic effects ofcannabinoids,whichnow constitutes a widely debated issue with amplescientific,clinical and social relevance.The scientificcommunity has gained substantial knowledge ofthe pal-liative and antitumour actions ofcannabinoids duringthe past few years.However,further basic research andmore exhaustive clinical trials are still required beforecannabinoids can be routinely used in cancer therapy.
Cannabinoids and their receptors
The hemp plant
Cannabis sativa 
produces ~60unique compounds known as cannabinoids.Although the pharmacology ofmost ofthe cannabi-noids is unknown,it is widely accepted that
9
-tetrahydrocannabinol (THC) is the most impor-tant,owing to its high potency and abundance incannabis
1
.Other relevant plant-derived cannabinoidsinclude
8
-THC,which is almost as active as
9
-THCbut less abundant;cannabinol,which is produced inlarge amounts but is a weak 
CANNABIMIMETIC
agent;and
CANNABIDIOL
,which is abundant but has nocannabimimetic activity.THC exerts a wide variety of biological effects by mimicking endogenoussubstances — the endocannabinoids anandamideand 2-arachidonoylglycerol —that activate specificcannabinoid receptors
(BOX 1)
.So far,two cannabinoid-specific receptors —CB
1
andCB
2
— have been cloned and characterized frommammalian tissues
2
.Both the central effects and manyofthe peripheral effects ofcannabinoids depend onCB
1
-receptor activation.Expression ofthis receptor isabundant in the brain,particularly in discrete areasthat are involved in the control ofmotor activity (basalganglia and cerebellum),memory and cognition (cor-tex and hippocampus),emotion (amygdala),sensoryperception (thalamus),and autonomic and endocrinefunctions (hypothalamus,pons and medulla),but theCB
1
receptor is also expressed in peripheral nerve ter-minals and various extraneural sites such as the testis,eye,vascular endothelium and spleen.By contrast,theCB
2
receptor is almost exclusively expressed in theimmune system,both by cells,including B and T lym-phocytes and macrophages,and by tissues,includingthe spleen,tonsils and lymph nodes
2–4
.Other than the endocannabinoids,there are threemain structural classes ofcannabinoid-agonist ligands.These are the ‘classical’cannabinoid analogues ofTHC,the ‘non-classical’bicyclic and tricyclic cannabinoidanalogues ofTHC,and the aminoalkylindoles.All have
CANNABINOIDS:POTENTIALANTICANCER AGENTS
Manuel Guzmán 
Cannabinoids — the active components of
Cannabis sativa 
and their derivatives — exertpalliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulatingappetite. In addition, these compounds have been shown to inhibit the growth of tumour cells inculture and animal models by modulating key cell-signalling pathways. Cannabinoids are usuallywell tolerated, and do not produce the generalized toxic effects of conventional chemotherapies.So, could cannabinoids be used to develop new anticancer therapies?
CANNABINOIDS
Compounds withtetrahydrocannabinol (THC)-like structures and/or THC-likepharmacological properties.Many compounds with a THC-like structure are present incannabis,but not all ofthemhave THC-like pharmacologicalproperties.In addition,somenatural or synthetic compoundshave THC-like pharmacologicalproperties but not THC-likestructure.
CANNABIMIMETIC
Tetrahydrocannabinol (THC)-like in pharmacological terms.Acompound is usually accepted ascannabimimetic ifit producesfour characteristic THC effectsin an
in vivo 
assay known as themouse tetrad model’:hypomotility,hypothermia,analgesia and a sustainedimmobility ofposture(catalepsy).NATURE REVIEWS
|
CANCER
VOLUME 3
|
OCTOBER2003
|
745
Department ofBiochemistrand Molecular Biology I,School ofBiology,Complutense University,28040 Madrid,Spain.e-mail: mgp@bbm1.ucm.es 
doi:10.1038/nrc1188
REVIEWS
 
CANNABIDIOL
A non-psychoactivecannabinoid present in cannabisthat inhibits convulsions,anxiety,vomiting andinflammation;it is now in PhaseIII clinical trials in combinationwith tetrahydrocannabinol forthe treatment ofmultiple-sclerosis-associated muscledisorders.
MYENTERIC AND SUBMUCOSALPLEXUS
A network ofsympathetic andparasympathetic nerve fibresand neuron cell bodies that aretucked in among the intersticesofthe smooth-muscle layersurrounding the digestivemucosa (myenteric plexus) or just underneath the digestivemucosa (submucosal plexus)and that coordinately controlgastrointestinal contractions.
META-ANALYSIS
Statistical analysis ofa largecollection ofresults fromindividual studies for thepurpose ofintegrating theirfindings.
746
|
OCTOBER2003
|
VOLUME 3
www.nature.com/reviews/cancer
REVIEWS
 
Cannabinoids are antiemetic in animal models of vomiting
6
.As the CB
1
receptor is present in cholinergicnerve terminals ofthe
MYENTERICANDSUBMUCOSAL PLEXUS
ofthe stomach,duodenum and colon,it is probablethat cannabinoid-induced inhibition ofdigestive-tract motility is caused by blockade ofacetylcholinerelease in these areas
6
.There is also evidence thatcannabinoids act on CB
1
receptors that are localizedin the dorsal–vagal complex ofthe brainstem — theregion ofthe brain that controls the vomiting reflex— and that endocannabinoids and their inactivat-ing enzymes are present in the gastrointestinal tractand might have a physiological role in the controlofemesis
6,7
.One ofthe earliest studied,and so far the bestestablished,therapeutic benefits ofcannabinoids inhumans is the treatment ofnausea and vomiting.Agreat number ofclinical trials with THC,syntheticcannabinoids and cannabis smoking in the 1970s and1980s showed that the antiemetic potency ofcannabi-noids was at least equivalent to that ofthe antiemeticswidely used at that time,such as the dopamineD
2
-receptor antagonists prochlorperazine,domperi-done and metoclopramide
8–10
.In addition,most ofthepatients tested had a clear preference for cannabinoidsas antiemetics.
META-ANALYSIS
indicates that an optimalbalance ofefficacy and unwanted effects was achievedwith relatively modest doses ofTHC (~5.0 mg/day),and that the dose could be increased duringchemotherapy cycles
8–10
.Today,capsules ofTHC(dronabinol (Marinol)) and its classical synthetic ana-logue LY109514 (nabilone (Cesamet)) are approved totreat nausea and emesis associated with cancerchemotherapy
(TABLE 1)
.Nabilone also inhibits nauseaand vomiting associated with radiation therapy andanaesthesia after abdominal surgery.However,theeffect ofnabilone in these treatments is moderate
8–10
.Although it is clear that cannabinoids serve as anti-emetic agents in cancer therapy,several questionsremain to be answered
9
.Cannabinoids should be com-pared alone and in combination with modern anti-emetics,such as the selective serotonin 5-HT
3
-receptorantagonist ondansetron and the selective substanceP/neurokinin-1-receptor antagonist aprepitant,whichhave fewer associated side effects than the antiemeticsthat were used when the original cannabinoid trialswere carried out.Ofinterest,cannabinoids are rela-tively effective in preventing nausea and emesis inpatients during the delayed phase ofchemotherapy-induced emesis,which usually occurs 24 hours or moreafter chemotherapy and is poorly controlled in abouthalfofthe patients receiving 5-HT
3
-receptor antago-nists
6,7
.The reason for this distinct behaviour of cannabinoids and 5-HT
3
-receptor antagonistsisunknown,but might be because ofthe different patho-physiological bases ofacute and delayed emesis.Inaddition,it is worth noting that cannabinoids can block 5-HT
3
receptors
11
.Further studies will be required toestablish which patients and what types ofcancerchemotherapy are suited to cannabinoid use for theprevention ofnausea and emesis.been subjected to comprehensive structure–activityrelationship studies,which,by selectively modifying thechemical structure ofcannabinoid molecules,have ledto the generation ofvarious types ofpotent syntheticcannabinoid-receptor agonists.Selective cannabinoid-receptor antagonists such as the diarylpyrazoles (proto-typical compounds developed by Sanofi:for example,SR141716 for CB
1
and SR144528 for CB
2
) have alsobeen developed
2,5
.All ofthese compounds have beenexcellent pharmacological tools that have been used toachieve a detailed knowledge ofcannabinoid action,and might serve as templates for the design ofclinicallyuseful drugs.
Palliative effects of cannabinoids
Cannabinoids have been known to exert palliativeeffects in oncology since the early 1970s,and for thisreason they are given to patients — although quiterestrictedly — in the clinic.The molecular basis oftheestablished and potential palliative applications of cannabinoids are still being dissected.
Inhibition ofnausea and emesis.
Prolonged nauseaand emesis/vomiting is a devastating side effect thatregularly accompanies the administration ofcancerchemotherapeutic drugs.This unwanted effect can beso severe that some patients stop their treatmentsdespite the persistence ofmalignant cancer.Whennausea and vomiting are frequent,antiemetic drugsare routinely given before and after chemotherapy.
Summary
Cannabinoids,the active components of 
Cannabissativa 
and their derivatives,act inthe organism by mimicking endogenous substances,the endocannabinoids,thatactivate specific cannabinoid receptors.Cannabinoids exert palliative effects inpatients with cancer and inhibit tumour growth in laboratory animals.The best-established palliative effect ofcannabinoids in cancer patients is theinhibition ofchemotherapy-induced nausea and vomiting.Today,capsules of 
9
-tetrahydrocannabinol (dronabinol (Marinol)) and its synthetic analogue nabilone(Cesamet) are approved for this purpose.Other potential palliative effects ofcannabinoids in cancer patients — supported byPhase III clinical trials — include appetite stimulation and pain inhibition.In relationto the former,dronabinol is now prescribed for anorexia associated with weight loss inpatients with AIDS.Cannabinoids inhibit tumour growth in laboratory animals.They do so bymodulating key cell-signalling pathways,thereby inducing direct growth arrest anddeath oftumour cells,as well as by inhibiting tumour angiogenesis and metastasis.Cannabinoids are selective antitumour compounds,as they can kill tumour cellswithout affecting their non-transformed counterparts.It is probable that cannabinoidreceptors regulate cell-survival and cell-death pathways differently in tumour and non-tumour cells.Cannabinoids have favourable drug-safety profiles and do not produce the generalizedtoxic effects ofconventional chemotherapies.The use ofcannabinoids in medicine,however,is limited by their psychoactive effects,and so cannabinoid-based therapiesthat are devoid ofunwanted side effects are being designed.Further basic and preclinical research on cannabinoid anticancer properties isrequired.It would be desirable that clinical trials could accompany these laboratorystudies to allow us to use these compounds in the treatment ofcancer.
 
NATURE REVIEWS
|
CANCER
VOLUME 3
|
OCTOBER2003
|
747
REVIEWS
 
increase food intake in animals.These effects are par-ticularly seen when cannabinoids are administered atlow to moderate doses,which do not produce markedside effects
13
.The endogenous cannabinoid systemmight serve as a physiological regulator offeedingbehaviour.For example,endocannabinoids and CB
1
receptors are present in the hypothalamus,the area of the brain that controls food intake;hypothalamicendocannabinoid levels are reduced by leptin,one of the main anorexic hormones;and blockade oftonicendocannabinoid signalling with the CB
1
antagonist
Appetite stimulation.
More than halfofthe patients withadvanced cancer experience lack ofappetite and/orweight loss,and they consistently rank anorexia as one of the most troublesome symptoms.Anorexia might ulti-mately lead to massive weight loss — cachexia — whichis an important risk factor for morbidity and mortalityin cancer.About one-third ofcancer patients lose morethan 5% oftheir original body weight,and cachexia isestimated to account for ~20% ofcancer deaths
12
.Many studies have reported that THC and othercannabinoids have a stimulatory effect on appetite and
IONOTROPIC RECEPTORS
Channel-like receptors that areopened by agonist binding andthrough which ions such as Na
+
,K
+
and/or Ca
2+
can pass.Ionotropic glutamate receptorsare usually divided into threegroups:
-methyl-
D
-asparticacid (NMDA) receptors,kainatereceptors and
α
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)receptors.
METABOTROPIC RECEPTORS
Seven-transmembrane(heptahelical) receptors thatcouple to heterotrimeric Gproteins,thereby modulatingpathways such as cyclicAMP–protein kinase A (via G
s
orG
i
),diacylglycerol–proteinkinase C (via G
q
) and inositol1,4,5-trisphosphate–Ca
2+
(viaG
q
).At least eight subtypes of glutamate metabotropicreceptors are known.
INTRAOCULAR PRESSURE
Pressure inside the eye.When itincreases
— 
for example,inglaucoma
— 
damage to theoptic nerve ofthe eye can resultin blindness.Cannabinoidsdecrease intraocular pressure.
Box 1 |
The endogenous cannabinoid system
Plant-derived cannabinoids such as
9
-tetrahydrocannabinol (THC),as well as their synthetic analogues,act in theorganism by activating specific cell-surface receptors that are normally engaged by a family ofendogenous ligands —the endocannabinoids (see figure).The first endocannabinoid discovered was named anandamide (AEA),from thesanscrit ananda,‘internal bliss’,and with reference to its chemical structure — arachidonoylethanolamide,the amide of arachidonic acid (AA) and ethanolamine (Et)
100
.A second arachidonic-acid derivative (2-arachidonoylglycerol (2-AG))that binds to cannabinoid receptors was subsequently described
101,102
.These endocannabinoid ligands,together withtheir receptors
103,104
and specific processes ofsynthesis
105,106
,uptake
107
and degradation
108
,constitute the endogenouscannabinoid system.A well-established function ofthe endogenous cannabinoid system is its role in brain neuromodulation.Postsynapticneurons synthesize membrane-bound endocannabinoid precursors and cleave them to release activeendocannabinoids following an increase ofcytosolic free Ca
2+
concentrations:for example,after binding oneurotransmitters (NTs) to their
IONOTROPIC
(iR) or
METABOTROPIC
(mR) receptors
109
.Endocannabinoids subsequentlyact as retrograde messengers by binding to presynaptic CB
1
cannabinoid receptors,which are coupled to the inhibitionofvoltage-sensitive Ca
2+
channels and the activation ofK
+
channels
110
.This blunts membrane depolarization andexocytosis,thereby inhibiting the release ofNTs such as glutamate,dopamine and
γ 
-aminobutyric acid (GABA) andaffecting,in turn,processes such as learning,movement and memory,respectively
111
.Endocannabinoidneuromodulatory signalling is terminated by an unidentified membrane-transport system
107
(T) and a family of intracellular degradative enzymes,the best characterized ofwhich is fatty acid amide hydrolase (FAAH),whichdegrades AEA to AA and Et
108
.The endogenous cannabinoid system might also exert modulatory functions outside thebrain,both in the peripheral nervous system and in extraneural sites,controlling processes such as peripheral pain,vascular tone,
INTRAOCULAR PRESSURE
and immune function.
iRmRNTPrecursorAEA or2-AGT
Ca
2+
Ca
2+
, K
+
CB
1
 _
Presynaptic neuronPostsynaptic neuronEt, AA+
Plant-derived cannabinoidEndogenous cannabinoids
OOH
9
-Tetrahydrocannabinol (THC)
OOOOHOHNHO
Anandamide (AEA)2-Arachidonoylglycerol (2-AG)FAAH

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