Cannabinoid pharmacology in cancer research: A new hope for cancer patients?

Abstract

Cannabinoids have been used for many centuries to ease pain and in the past decade, the endocannabinoid system has been implicated in a number of pathophysiological conditions, such as mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis, spinal cord injury, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity, and osteoporosis. Several studies have demonstrated that cannabinoids also have anti-cancer activity and as cannabinoids are usually well tolerated and do not produce the typical toxic effects of conventional chemotherapies, there is considerable merit in the development of cannabinoids as potential anticancer therapies. Whilst the presence of psychoactive effects of cannabinoids could prevent any progress in this field, recent studies have shown the value of the non-psychoactive components of cannabinoids in activating apoptotic pathways, inducing anti-proliferative and anti-angiogenic effects. The aforementioned effects are suggested to be through pathways such as ERK, Akt, mitogen-activated protein kinase (MAPK) pathways, phosphoinositide 3-kinase (PI3K) pathways and hypoxia inducible factor 1 (HIF1), all of which are important contributors to the hallmarks of cancer. Many important questions still remain unanswered or are poorly addressed thus necessitating further research at basic pre-clinical and clinical levels. In this review, we address these issues with a view to identifying the key challenges that future research needs to address.

The current state and future perspectives of cannabinoids in cancer biology

“…The first report of antiproliferative properties of cannabinoids comes from 1975, when Munson et al demonstrated that Δ 9 -tetrahydrocannabinol inhibits lung adenocarcinoma cell growth of in vitro cell line and in murine model after oral administration [30]. Many cannabinoids, ranging from phytocannabinoids (THC, CBD), endocannabinoids (2-arachidonoylglycerol, anandamide), to synthetic cannabinoids (JWH-133, WIN-55,212-2), have shown ability to inhibit proliferation, metastasis, and angiogenesis in a variety of models of cancer [7,8]. On the other hand, there are reports that have indicated that under certain circumstances, cannabinoids can be protumorigenic [31][32][33].…”

The Endocannabinoid System: A Target for Cancer Treatment

“…On the other hand, antiproliferative and pro-apoptotic effects of both CB1 and CB2 agonists have been attributed also to their ability to increase the synthesis of the pro-apoptotic sphingolipid ceramide. In leukemic cells, ceramide can induce apoptosis by regulation of p38 MAPK (mitogen-activated protein kinase) signaling, while in glioma cells it up-regulates the endoplasmic reticulum (ER) stress-related gene, those encoding the transcription factors activating transcription factor 4 (ATF-4) and C/EBP homologous protein (CHOP), and the stress-related pseudokinase [7] (Figure 1). In lung cancer, the ceramide-dependent pro-apoptotic effect triggered by AEA and CBD seems to be mediated by an up-regulation of cyclooxygenase 2 (Cox-2) expression and by the increased synthesis of the pro-apoptotic prostaglandin E-2 (PGE2) [8].…”

“…The fatty acid amide hydrolase (FAAH) is the catabolic enzyme mainly for AEA degradation and, with lower affinity, of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), while the major enzyme responsible for 2-AG degradation is monoacylglycerol lipase (MAGL). Interestingly, FAAH and MAGL expression were found upregulated in cancer tissues [7,8]. Other enzymes, like lysosomal hydrolase N-acylethanolamine hydrolyzing acid amidase (NAAA) that degrades AEA, OEA, and PEA, constitute potential targets in cancer [5].…”

Analysis of the potential correlation between gastric cancer and gastrointestinal microbiota via in-silico data mining

“…Drugs targeting the endocannabinoid system may have anti-metastatic effect to function against various types of tumors (45). Other functions of cannabinoid include antiapoptotic, anti-angiogenic and anti-proliferative in the cancer cell growth through multiple pathways such as ERK, Akt, MAPK, PI3K and HIF-1 (46). The endocannabinoid signaling is also reported to play a role in inflammation (47), energy balance (47), gastric barrier (48), adipogenesis (48), and neuroimmune disorder(49) by modulating the gastric microbiota.…”