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Cannabinoids: potential anticancer agents

Nature Reviews Cancer volume 3, pages 745–755 (2003)Cite this article

Key Points

  • Cannabinoids, the active components of Cannabis sativa and their derivatives, act in the organism by mimicking endogenous substances, the endocannabinoids, that activate specific cannabinoid receptors.

  • Cannabinoids exert palliative effects in patients with cancer and inhibit tumour growth in laboratory animals.

  • The best-established palliative effect of cannabinoids in cancer patients is the inhibition of chemotherapy-induced nausea and vomiting. Today, capsules of Δ9-tetrahydrocannabinol (dronabinol (Marinol)) and its synthetic analogue nabilone (Cesamet) are approved for this purpose.

  • Other potential palliative effects of cannabinoids in cancer patients — supported by Phase III clinical trials — include appetite stimulation and pain inhibition. In relation to the former, dronabinol is now prescribed for anorexia associated with weight loss in patients with AIDS.

  • Cannabinoids inhibit tumour growth in laboratory animals. They do so by modulating key cell-signalling pathways, thereby inducing direct growth arrest and death of tumour cells, as well as by inhibiting tumour angiogenesis and metastasis.

  • Cannabinoids are selective antitumour compounds, as they can kill tumour cells without affecting their non-transformed counterparts. It is probable that cannabinoid receptors 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 generalized toxic effects of conventional chemotherapies. The use of cannabinoids in medicine, however, is limited by their psychoactive effects, and so cannabinoid-based therapies that are devoid of unwanted side effects are being designed.

  • Further basic and preclinical research on cannabinoid anticancer properties is required. It would be desirable that clinical trials could accompany these laboratory studies to allow us to use these compounds in the treatment of cancer.

Abstract

Cannabinoids — the active components of Cannabis sativa and their derivatives — exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies. So, could cannabinoids be used to develop new anticancer therapies?

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Figure 1: Signalling pathways involved in the control of cell fate by cannabinoids.
Figure 2: Differential cannabinoid signalling in transformed versus non-transformed glial cells.

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Acknowledgements

I am indebted to all my laboratory colleagues, in particular to I. Galve-Roperh, G. Velasco and C. Sanchez for their continuous support and for making our research projects possible. This work was funded by 'Fundación Científica de la Asociación Española Contra el Cáncer' and 'Ministerio de Ciencia y Tecnología'.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, 28040, Spain

    Manuel Guzmán

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  1. Manuel Guzmán
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DATABASES

Cancer.gov

Glioblastoma multiforme

breast cancer

leukaemia

lymphomas

lung cancer

prostate cancer

skin cancer

thyroid cancer

LocusLink

adenylyl cyclase

AKT

CB1

CB2

EGF

ERK

FAAH

FAN

interferon-γ

interleukin-12

JNK

KRAS

matrix metalloproteinase-2

NF-κB

NGF

NOS

p38 MAPK

PI3K

RAF1

VEGF

FURTHER INFORMATION

British Medical Association (Therapeutic uses of cannabis)

GW Pharmaceuticals clinical trials

House of Lords Committee on Science and Technology (therapeutic uses of cannabis)

House of Lords Committee on Science and Technology (therapeutic uses of cannabis)

House of Lords Committee on Science and Technology (therapeutic uses of cannabis)

International Cannabinoid Research Society

IUPHAR Receptor Database

MRC multiple sclerosis clinical trial

Pharmos (dexanabinol)

RxMed (nabilone)

Sanofi–Synthelabo (rimonabant)

Unimed (dronabinol)

Glossary

CANNABINOIDS

Compounds with tetrahydrocannabinol (THC)-like structures and/or THC-like pharmacological properties. Many compounds with a THC-like structure are present in cannabis, but not all of them have THC-like pharmacological properties. In addition, some natural or synthetic compounds have THC-like pharmacological properties but not THC-like structure.

CANNABIMIMETIC

Tetrahydrocannabinol (THC)-like in pharmacological terms. A compound is usually accepted as cannabimimetic if it produces four characteristic THC effects in an in vivo assay known as the 'mouse tetrad model': hypomotility, hypothermia, analgesia and a sustained immobility of posture (catalepsy).

CANNABIDIOL

A non-psychoactive cannabinoid present in cannabis that inhibits convulsions, anxiety, vomiting and inflammation; it is now in Phase III clinical trials in combination with tetrahydrocannabinol for the treatment of multiple-sclerosis-associated muscle disorders.

MYENTERIC AND SUBMUCOSAL PLEXUS

A network of sympathetic and parasympathetic nerve fibres and neuron cell bodies that are tucked in among the interstices of the smooth-muscle layer surrounding the digestive mucosa (myenteric plexus) or just underneath the digestive mucosa (submucosal plexus) and that coordinately control gastrointestinal contractions.

META-ANALYSIS

Statistical analysis of a large collection of results from individual studies for the purpose of integrating their findings.

IONOTROPIC RECEPTORS

Channel-like receptors that are opened by agonist binding and through which ions such as Na+, K+ and/or Ca2+ can pass. Ionotropic glutamate receptors are usually divided into three groups: N-methyl-D-aspartic acid (NMDA) receptors, kainate receptors and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors.

METABOTROPIC RECEPTORS

Seven-transmembrane (heptahelical) receptors that couple to heterotrimeric G proteins, thereby modulating pathways such as cyclic AMP–protein kinase A (via Gs or Gi), diacylglycerol–protein kinase C (via Gq) and inositol 1,4,5-trisphosphate–Ca2+ (via Gq). At least eight subtypes of glutamate metabotropic receptors are known.

INTRAOCULAR PRESSURE

Pressure inside the eye. When it increases — for example, in glaucoma — damage to the optic nerve of the eye can result in blindness. Cannabinoids decrease intraocular pressure.

NOCICEPTIVE

A stimulus that causes pain or a reaction that is caused by pain.

HYPERALGESIA

An increased sensitivity and lowered threshold to a stimulus — such as burn of the skin — that is normally painful.

ALLODYNIA

Pain caused by a stimulus — such as touch, pressure and warmth — that does not normally provoke pain.

SENSORY-MOTOR PERIPHERAL NEUROPATHIES

Diseases or abnormalities of the peripheral nervous system that affect senses and movement.

MYASTHENIC

Abnormal muscle weakness or fatigue.

FORKHEAD TRANSCRIPTION FACTORS

A family of proteins that regulate the expression of genes that are involved in the control of cell survival, death, growth, differentiation and stress responses. Their activity is tightly controlled by AKT, so that phosphorylated forkhead transcription factor FOXO is retained in the cytoplasm and remains transcriptionally inactive.

PHEOCHROMOCYTOMA

A relatively severe tumour of adrenal-gland chromaffin cells that causes excess release of adrenaline and noradrenaline and is therefore characterized by hypertension and tachycardia.

PHARMACODYNAMICS

Mechanisms by which drugs affect their target sites in the body to produce their desired therapeutic effects and their adverse side effects.

PHARMACOKINETICS

Time course of drug and metabolite levels in different fluids, tissues and excreta of the body, and of the mathematical relationships required to develop models to interpret such data.

FIRST-PASS METABOLISM

Pre-systemic metabolism of a drug that limits its exposure to the body. For example, chemical or enzymatic breakdown of a drug in the gastrointestinal lumen or in the stomach, intestine or liver cells can greatly reduce the amount of drug that ends up in the bloodstream.

DEXANABINOL

(HU-211). A non-psychoactive synthetic derivative of tetrahydrocannabinol that blocks ionotropic glutamate receptors and has antioxidant and anti-inflammatory properties; it is now in Phase III clinical trials for the management of brain trauma.

AJULEMIC ACID

(CT3). A synthetic derivative of the tetrahydrocannabinol metabolite 11-carboxy-THC that inhibits pain and inflammation; it is entering Phase II clinical trials for the treatment of pain and spasticity in multiple sclerosis.

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Guzmán, M. Cannabinoids: potential anticancer agents. Nat Rev Cancer 3, 745–755 (2003). https://doi.org/10.1038/nrc1188

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