Cannabinoid Receptor-1 suppresses M2 macrophage polarization in colorectal cancer by downregulating EGFR

Cell Death Discovery

“Cannabinoid receptors, CB1 and CB2, have been implicated as emerging targets for cancer therapy. Herein, we investigated the potential regulation mechanism of CB1 and its implications in colorectal cancer. CB1 and EGFR expression were examined in colorectal cancer cell lines. The effects of CB1 agonist ACEA and its antagonist AM251 on the proliferation, migration and invasion of colorectal cancer cells and the expression of M1 and M2 macrophage markers were examined. EGFR overexpression was performed with plasmids containing EGFR gene. Tumor xenografts were constructed to explore the effects of CB1 activation on tumorigenesis. We showed that CB1 was downregulated while EGFR was upregulated in colorectal cancer cells. The activation of CB1 suppressed the proliferation, migration and invasion of colorectal cancer cells and the differentiation of M2 macrophages, while CB1 inhibition had opposite effects. Moreover, the alterations in tumorigenesis and M2 macrophage activation induced by CB1 activation were counteracted by EGFR overexpression. Besides, CB1 silencing promoted tumor cell proliferation and M2 polarization which was counteracted by EGFR knockdown. In vivo, CB1 activation also repressed tumorigenesis and M2 macrophage activation. The present study demonstrated that CB1 activation suppressed M2 macrophage through EGFR downregulation in colorectal cancers. These findings first unveiled the potential avenue of CB1 as a targeted therapy for colorectal cancer.”

https://pubmed.ncbi.nlm.nih.gov/35641479/

“In conclusion, our study showed that CB1 activation suppressed tumor growth and M2 macrophage activation in colorectal cancer by downregulating EGFR. Our study provided the first evidence that CB1 activation was capable to suppress M2 macrophage activation. Since M2 macrophage are linked with immune evasion in various cancers, CB1 might be a promising target for cancer treatment.”

https://www.nature.com/articles/s41420-022-01064-8

“The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy.”

https://pubmed.ncbi.nlm.nih.gov/17583570/

The Effectiveness and Safety of Medical Cannabis for Treating Cancer Related Symptoms in Oncology Patients

Frontiers in Pain Research (@FrontPain) / Twitter

“The use of medical cannabis (MC) to treat cancer-related symptoms is rising. However, there is a lack of long-term trials to assess the benefits and safety of MC treatment in this population. In this work, we followed up prospectively and longitudinally on the effectiveness and safety of MC treatment.

Oncology patients reported on multiple symptoms before and after MC treatment initiation at one-, three-, and 6-month follow-ups. Oncologists reported on the patients’ disease characteristics. Intention-to-treat models were used to assess changes in outcomes from baseline. MC treatment was initiated by 324 patients and 212, 158 and 126 reported at follow-ups.

Most outcome measures improved significantly during MC treatment for most patients (p < 0.005). Specifically, at 6 months, total cancer symptoms burden declined from baseline by a median of 18%, from 122 (82–157) at baseline to 89 (45–138) at endpoint (−18.98; 95%CI= −26.95 to −11.00; p < 0.001). Reported adverse effects were common but mostly non-serious and remained stable during MC treatment.

The results of this study suggest that MC treatment is generally safe for oncology patients and can potentially reduce the burden of associated symptoms with no serious MC-related adverse effects.

The main finding of the current study is that most cancer comorbid symptoms improved significantly during 6 months of MC treatment.

Additionally, we found that MC treatment in cancer patients was well tolerated and safe.”

https://pubmed.ncbi.nlm.nih.gov/35669038/

https://www.frontiersin.org/articles/10.3389/fpain.2022.861037/full?utm_source=fweb


Cannabidiol exerts anti-proliferative activity via a cannabinoid receptor 2-dependent mechanism in human colorectal cancer cells

International Immunopharmacology

“Colorectal cancer is the third leading cause of cancer incidence and mortality in the United States. Cannabidiol (CBD), the second most abundant phytocannabinoid in Cannabis sativa, has potential use in cancer treatment on the basis of many studies showing its anti-cancer activity in diverse types of cancer, including colon cancer. However, its mechanism of action is not yet fully understood.

In the current study, we observed CBD to repress viability of different human colorectal cancer cells in a dose-dependent manner. CBD treatment led to G1-phase cell cycle arrest and an increased sub-G1 population (apoptotic cells); it also downregulated protein expression of cyclin D1, cyclin D3, cyclin-dependent kinase 2 (CDK2), CDK4, and CDK6. CBD further increased caspase 3/7 activity and cleaved poly(ADP-ribose) polymerase, and elevated expression of endoplasmic reticulum (ER) stress proteins including binding immunoglobulin protein (BiP), inositol-requiring enzyme 1α (IRE1α), phosphorylated eukaryotic initiation factor 2α (eIF2α), activating transcription factor 3 (ATF3), and ATF4.

We found that CBD repressed cell viability and induced apoptotic cell death through a mechanism dependent on cannabinoid receptor type 2 (CB2), but not on CB1, transient receptor potential vanilloid, or peroxisome proliferator-activated receptor gamma. Anti-proliferative activity was also observed for other non-psychoactive cannabinoid derivatives including cannabidivarin (CBDV), cannabigerol (CBG), cannabicyclol (CBL), and cannabigerovarin (CBGV). Our data indicate that CBD and its derivatives could be promising agents for the prevention of human colorectal cancer.”

https://pubmed.ncbi.nlm.nih.gov/35598400/

“CBD represses viability of human colorectal cancer cells.•

CBD induces cell cycle arrest and increases apoptosis and ER stress in human colorectal cancer cells.•

CBD represses cell viability and induces apoptotic cell death via a CB2-dependent mechanism.”

https://www.sciencedirect.com/science/article/pii/S1567576922003496?via%3Dihub


The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies

“Despite the long history of cannabinoid use for medicinal and ritual purposes, an endogenous system of cannabinoid-controlled receptors, as well as their ligands and the enzymes that synthesise and degrade them, was only discovered in the 1990s. Since then, the endocannabinoid system has attracted widespread scientific interest regarding new pharmacological targets in cancer treatment among other reasons. Meanwhile, extensive preclinical studies have shown that cannabinoids have an inhibitory effect on tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition (EMT) and induce tumour cell apoptosis and autophagy as well as immune response. Appropriate cannabinoid compounds could moreover be useful for cancer patients as potential combination partners with other chemotherapeutic agents to increase their efficacy while reducing unwanted side effects. In addition to the direct activation of cannabinoid receptors through the exogenous application of corresponding agonists, another strategy is to activate these receptors by increasing the endocannabinoid levels at the corresponding pathological hotspots. Indeed, a number of studies accordingly showed an inhibitory effect of blockers of the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on tumour development and spread. This review summarises the relevant preclinical studies with FAAH and MAGL inhibitors compared to studies with cannabinoids and provides an overview of the regulation of the endocannabinoid system in cancer.”

https://pubmed.ncbi.nlm.nih.gov/34830856/

Plant-derived cannabinoids as anticancer agents

“Substantial preclinical evidence demonstrates the antiproliferative, cytotoxic, and antimetastatic properties of plant-derived cannabinoids (phytocannabinoids) such as cannabidiol and tetrahydrocannabinol. The cumulative body of research into the intracellular mechanisms and phenotypic effects of these compounds supports a logical, judicious progression to large-scale phase II/III clinical trials in certain cancer types to truly assess the efficacy of phytocannabinoids as anticancer agents.”

https://pubmed.ncbi.nlm.nih.gov/35260379/

Cannabinoids as anticancer drugs: current status of preclinical research

“Drugs that target the endocannabinoid system are of interest as pharmacological options to combat cancer and to improve the life quality of cancer patients. From this perspective, cannabinoid compounds have been successfully tested as a systemic therapeutic option in a number of preclinical models over the past decades. As a result of these efforts, a large body of data suggests that the anticancer effects of cannabinoids are exerted at multiple levels of tumour progression via different signal transduction mechanisms. Accordingly, there is considerable evidence for cannabinoid-mediated inhibition of tumour cell proliferation, tumour invasion and metastasis, angiogenesis and chemoresistance, as well as induction of apoptosis and autophagy. Further studies showed that cannabinoids could be potential combination partners for established chemotherapeutic agents or other therapeutic interventions in cancer treatment. Research in recent years has yielded several compounds that exert promising effects on tumour cells and tissues in addition to the psychoactive Δ9-tetrahydrocannabinol, such as the non-psychoactive phytocannabinoid cannabidiol and inhibitors of endocannabinoid degradation. This review provides an up-to-date overview of the potential of cannabinoids as inhibitors of tumour growth and spread as demonstrated in preclinical studies.”

https://pubmed.ncbi.nlm.nih.gov/35277658/

Cannabidiol and Other Phytocannabinoids as Cancer Therapeutics

“Preclinical models provided ample evidence that cannabinoids are cytotoxic against cancer cells. Among the best studied phytocannabinoids, cannabidiol (CBD) is most promising for the treatment of cancer as it lacks the psychotomimetic properties of delta-9-tetrahydrocannabinol (THC). In vitro studies and animal experiments point to a concentration- (dose-)dependent anticancer effect. The effectiveness of pure compounds versus extracts is the subject of an ongoing debate. Actual results demonstrate that CBD-rich hemp extracts must be distinguished from THC-rich cannabis preparations. Whereas pure CBD was superior to CBD-rich extracts in most in vitro experiments, the opposite was observed for pure THC and THC-rich extracts, although exceptions were noted. The cytotoxic effects of CBD, THC and extracts seem to depend not only on the nature of cannabinoids and the presence of other phytochemicals but also largely on the nature of cell lines and test conditions. Neither CBD nor THC are universally efficacious in reducing cancer cell viability. The combination of pure cannabinoids may have advantages over single agents, although the optimal ratio seems to depend on the nature of cancer cells; the existence of a ‘one size fits all’ ratio is very unlikely. As cannabinoids interfere with the endocannabinoid system (ECS), a better understanding of the circadian rhythmicity of the ECS, particularly endocannabinoids and receptors, as well as of the rhythmicity of biological processes related to the growth of cancer cells, could enhance the efficacy of a therapy with cannabinoids by optimization of the timing of the administration, as has already been reported for some of the canonical chemotherapeutics. Theoretically, a CBD dose administered at noon could increase the peak of anandamide and therefore the effects triggered by this agent. Despite the abundance of preclinical articles published over the last 2 decades, well-designed controlled clinical trials on CBD in cancer are still missing. The number of observations in cancer patients, paired with the anticancer activity repeatedly reported in preclinical in vitro and in vivo studies warrants serious scientific exploration moving forward.”

https://pubmed.ncbi.nlm.nih.gov/35244889/

Cannabis as a potential compound against various malignancies, legal aspects, advancement by exploiting nanotechnology and clinical trials

“Various preclinical and clinical studies exhibited the potential of cannabis against various diseases, including cancer and related pain. Subsequently, many efforts have been made to establish and develop cannabis-related products and make them available as prescription products. Moreover, FDA has already approved some cannabis-related products, and more advancement in this aspect is still going on. However, the approved product of cannabis is in oral dosage form, which exerts various limitations to achieve maximum therapeutic effects. A considerable translation is on a hike to improve bioavailability, and ultimately, the therapeutic efficacy of cannabis by the employment of nanotechnology. Besides the well-known psychotropic effects of cannabis upon the use at high doses, literature has also shown the importance of cannabis and its constituents in minimising the lethality of cancer in the preclinical models. This review discusses the history of cannabis, its legal aspect, safety profile, the mechanism by which cannabis combats with cancer, and the advancement of clinical therapy by exploiting nanotechnology. A brief discussion related to the role of cannabinoid in various cancers has also been incorporated. Lastly, the information regarding completed and ongoing trials have also been elaborated.”

https://pubmed.ncbi.nlm.nih.gov/35321629/

β-Caryophyllene Induces Apoptosis and Inhibits Angiogenesis in Colorectal Cancer Models

ijms-logo“Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels.

Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer.

BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions.

These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.”

https://pubmed.ncbi.nlm.nih.gov/34638895/

https://www.mdpi.com/1422-0067/22/19/10550

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer

cancers-logo“Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world’s disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.”

https://pubmed.ncbi.nlm.nih.gov/34503163/

“In recent years, multiple preclinical studies have shown that changes in endocannabinoid system signaling may have various effects on intestinal inflammation and colorectal cancer. However, not all tumors can respond to cannabinoid therapy in the same manner. Given that colorectal cancer is a heterogeneous disease with different genomic landscapes, experiments with cannabinoids should involve different molecular subtypes, emerging mutations, and various stages of the disease. We hope that this review can help researchers form a comprehensive understanding of cannabinoid interactions in colorectal cancer and intestinal bowel diseases. We believe that selecting a particular experimental model based on the disease’s genetic landscape is a crucial step in the drug discovery, which eventually may tremendously benefit patient’s treatment outcomes and bring us one step closer to individualized medicine.”

https://www.mdpi.com/2072-6694/13/17/4353