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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.
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Few plant species have been the subject of somuch scientific, clinical and social debate as
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
-tetrahydrocannabinol (THC) is the mostrelevant owing to its high potency and abun-dance in plant preparations
. THC exerts awide variety of biological effects by mimick-ing endogenous substances — the so-calledendocannabinoids (the two most studiedbeing anandamide
and 2-arachidonoyl-glycerol (2-AG)
) — that engage specificcell-surface cannabinoid receptors
.So far, two major cannabinoid-specificreceptors — CB1
and CB2 — have beencloned and characterized from mamma-lian tissues
. 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
. 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
, but more recently it has also been shown to be expressed inadditional cell types
. 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
.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
, the endocannabinoid system exertsother regulatory functions in the body, suchas the control of cardiovascular tone, energy metabolism, immunity and reproduc-tion
. 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
, and their best-established use isin the inhibition of chemotherapy-inducednausea and vomiting
. Today, capsules of THC, named dronabinol (Marinol; Solvay Pharmaceuticals), and its synthetic analogue
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.
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