Cannabinoids as Anticancer Agents

Highlights

•The endocannabinoid system may play a dual role on the regulation of tumor generation and progression.
•Administration of THC and other cannabinoids exert anticancer actions in animal models of cancer.
•THC and other cannabinoid receptor-ligands induce cancer cell death and inhibit tumor angiogenesis.
•Cannabinoids enhance the anticancer activity of other antineoplastic agents in animal models of cancer.
•Cannabinoids are currently being tested as anticancer agents in phase I/II clinical studies.

It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumor growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumor angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.

 

This is not the first time that a study has shown that cannabinoids may be useful as anticancer agents. Numerous reports highlighting potent activity in vitro [i.e. cells studied outside of the body] and in in vivo [i.e. cells studied inside the body] models have established it as a potential anticancer therapeutic agent in a number of cancer types through processes such as:

  • induction of apoptosis [i.e. programmed cell death]…
  • autophagy [i.e. “self-eating”/”self-destruction”] via engagement of the mitogen-activated protein kinase [i.e. an enzyme activated by an agent which induces mitosis, the process by which cells increase in number, which is how cancerous tumors form] and the endoplasmic reticulum [i.e. an organelle, or part of the cell, involved in protein and lipid synthesis] stress-related pathways…
  • antiangiogeni[sis] [i.e. preventing formation of blood vessels, which cancerous growths need to survive]…
  • anti-inflammatory [actions]
  • anti-migratory[actions]

While the authors note that the psychoactive nature of THC has increased controversy in consideration of cancer treatment with its use,” a pilot trial of its therapeutic use in patients with glioblastoma multiforme (GBM), an advanced type of glioma, showed feasibility without any overt psychoactive effects.”

Additionally, CBD seems to work through similar mechanisms as THC in terms of anti-tumor effects, except it may not exert effects through receptor activation as frequently as THC, and it does not cause psychoactive effects. Further, THC demonstrates analgesic, anti-emetic, and anti-inflammatory properties, whereas CBD possesses anti-psychotic, anti-seizure, and anti-anxiety properties. Together, these cannabinoids (and many more) work together to create an entourage effect that is much more powerful than any single cannabinoid.

 

 Changes in the expression of cannabinoid (CB) receptors or endocannabinoids (ECB)-degrading enzymes in human cancer.
Tumor type CB receptors or ECB degrading enzymes References
Hodgkin lymphoma CB1 levels increased (Benz et al., 2013)
Non-Hodgkin lymphoma CB1 levels increased (Gustafsson et al., 2008)
Chemically-induced cellular hepatocarcinoma CB1 levels increased (Mukhopadhyay et al., 2015)
Hepatocellular carcinoma CB1 and CB2 expression correlates with improved prognosis of patients with hepatocellular carcinoma {Xu, 2006 #378}
Human epithelial ovarian tumors CB1 levels increased. Correlation with disease severity (Messalli et al., 2014)
Stage IV colorectal cancer CB1 levels are a factor of bad prognosis following surgery (Jung et al., 2013)
Colon cancer CB1 levels decreased, CB1 genetic ablation increases the growth of colon carcinomas (Wang et al., 2008)
Pancreatic cancer CB1 and CB2 levels increased and MAGL and FAAH levels decreased associated with bad prognosis (Michalski et al., 2008)
Prostate cancer CB1 levels increased associated with severity of disease and poor prognosis (Chung et al., 2009)
Prostate cancer FAAH tumor levels (but not CB1) directly correlate with severity of the diseases (Thors et al., 2010)
Breast cancer CB2 levels increased. Correlation with disease severity {Caffarel, 2010 #15;Caffarel, 2006 #16;Perez-Gomez et al., 2015 #349}
Glioma CB2 levels increased with degree in gliomas (Sanchez et al., 2001)
Mantle cell lymphoma CB1 and CB2 levels increased and FAAH levels decreased (Ek et al., 2002; Islam et al., 2003; Wasik et al., 2011)
UV light induced skin carcinogenesis CB1 and CB2 genetic ablation decrease UV light induced skin carcinogenesis (Zheng et al., 2008)
Leukemia CB2 overexpression enhances the predisposition to leukemia after leukemia virus infection. (Joosten et al., 2002)
Glioma, breast cancer, skin cancer GPR55 increased levels associated with higher histological tumor grade (Andradas et al., 2011; Perez-Gomez et al., 2013)
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