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

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The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472

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Cancer Initiation, Progression and Resistance: Are Phytocannabinoids from Cannabis sativa L. Promising Compounds?

molecules-logo“Cannabis sativa L. is a source of over 150 active compounds known as phytocannabinoids that are receiving renewed interest due to their diverse pharmacologic activities. Indeed, phytocannabinoids mimic the endogenous bioactive endocannabinoids effects through activation of CB1 and CB2 receptors widely described in the central nervous system and peripheral tissues.

All phytocannabinoids have been studied for their protective actions towards different biological mechanisms, including inflammation, immune response, oxidative stress that, altogether, result in an inhibitory activity against the carcinogenesis.

The role of the endocannabinoid system is not yet completely clear in cancer, but several studies indicate that cannabinoid receptors and endogenous ligands are overexpressed in different tumor tissues.

Recently, in vitro and in vivo evidence support the effectiveness of phytocannabinoids against various cancer types, in terms of proliferation, metastasis, and angiogenesis, actions partially due to their ability to regulate signaling pathways critical for cell growth and survival.

The aim of this review was to report the current knowledge about the action of phytocannabinoids from Cannabis sativa L. against cancer initiation and progression with a specific regard to brain, breast, colorectal, and lung cancer as well as their possible use in the therapies. We will also report the known molecular mechanisms responsible for such positive effects.

Finally, we will describe the actual therapeutic options for Cannabis sativa L. and the ongoing clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/34063214/

https://www.mdpi.com/1420-3049/26/9/2668

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Cannabinoids pharmacological effects are beyond the palliative effects: CB2 cannabinoid receptor agonist induced cytotoxicity and apoptosis in human colorectal cancer cells (HT-29)

SpringerLink“Colorectal cancer (CRC) is between the top three occurring cancers worldwide. The anticancer effects of Cannabinoid receptor 2 (CB2) agonist (GW833972A) in the presence and absence of its inverse agonist (SR144528) on Human colorectal adenocarcinoma cells (HT-29) was investigated. Following cell viability assays on HT-29 and HFF cells, the molecular mechanism(s) of cytotoxicity and apoptotic pathways of cell death were analyzed. The anticancer effects of CB2 agonist were measured with tumor cell migration and colony-forming assays. Real-time PCR and Western blotting techniques were used to examine any alterations in the expression of apoptotic genes. A concentration and time-dependent cytotoxicity of CB2 agonist with IC50 value of 24.92 ± 6.99 μM was obtained. The rate of lipid peroxidation was elevated, while the TNF-α concentration was declined, significantly (p < 0.05). CB2 agonist (50 μM) reduced the colony-forming capability by 83% and tumor cell migration by 50%. Apoptotic effects of CB2 agonist were revealed with the increase of apoptotic cells in Acridine orange/Ethidium bromide staining, clear DNA fragmentation, pro-apoptotic genes and proteins upregulation (Caspase-3 and p53), and significant downregulation of anti-apoptotic Bcl-2. All assessments demonstrated that CB2 agonist-induced effects were reversed by CB2 inverse agonist. These data suggest that CB2 agonists at micro-molar concentrations might be considered in the CRC treatment, and their effectiveness attributes to the apoptosis induction via upregulation of caspase-3 and p53 and downregulation of Bcl-2.”

https://pubmed.ncbi.nlm.nih.gov/33886060/

https://link.springer.com/article/10.1007/s11010-021-04158-6

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Different Cannabis sativa Extraction Methods Result in Different Biological Activities against a Colon Cancer Cell Line and Healthy Colon Cells

plants-logo“Cannabis sativa is one of the oldest medicinal plants used by humans, containing hundreds of bioactive compounds. The biological effects and interplay of these compounds are far from fully understood, although the plant’s therapeutic effects are beyond doubt.

Extraction methods for these compounds are becoming an integral part of modern Cannabis-based medicine. Still, little is known about how different methods affect the final composition of Cannabis extracts and thus, their therapeutic effects.

In this study, different extraction methods were tested, namely maceration, Soxhlet, ultrasound-assisted extraction (UAE), and supercritical CO2 extraction methods. The obtained extracts were evaluated for their cannabinoid content, antioxidant properties, and in vitro bioactivity on human colon cancer and healthy colon cells.

Our data suggest that Cannabis extracts, when properly prepared, can significantly decrease cancer cell viability while protecting healthy cells from cytotoxic effects.

However, post-processing of extracts poses a significant limitation in predicting therapeutic response based on the composition of the crude extract, as it affects not only the actual amounts of the respective cannabinoids but also their relative ratio to the primary extracts. These effects must be carefully considered in the future preparations of new therapeutic extracts.”

https://pubmed.ncbi.nlm.nih.gov/33802757/

https://www.mdpi.com/2223-7747/10/3/566

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Cannabis and its Constituents for Cancer: History, Biogenesis, Chemistry and Pharmacological Activities

Pharmacological Research “Cannabis has long been used for healing and recreation in several regions of the world. Over 400 bioactive constituents, including more than 100 phytocannabinoids, have been isolated from this plant. The non-psychoactive cannabidiol (CBD) and the psychoactive Δ9-tetrahydrocannabinol (Δ9-THC) are the major and widely studied constituents from this plant.

Cannabinoids exert their effects through the endocannabinoid system (ECS) that comprises cannabinoid receptors (CB1, CB2), endogenous ligands, and metabolizing enzymes. Several preclinical studies have demonstrated the potential of cannabinoids against leukemia, lymphoma, glioblastoma, and cancers of the breast, colorectum, pancreas, cervix and prostate.

Cannabis and its constituents can modulate multiple cancer related pathways such as PKB, AMPK, CAMKK-β, mTOR, PDHK, HIF-1α, and PPAR-γ. Cannabinoids can block cell growth, progression of cell cycle and induce apoptosis selectively in tumour cells. Cannabinoids can also enhance the efficacy of cancer therapeutics. These compounds have been used for the management of anorexia, queasiness, and pain in cancer patients.

Cannabinoid based products such as dronabinol, nabilone, nabiximols, and epidyolex are now approved for medical use in cancer patients. Cannabinoids are reported to produce a favourable safety profile. However, psychoactive properties and poor bioavailability limit the use of some cannabinoids. The Academic Institutions across the globe are offering training courses on cannabis. How cannabis and its constituents exert anticancer activities is discussed in this article. We also discuss areas that require attention and more extensive research.”

https://pubmed.ncbi.nlm.nih.gov/33246167/

https://www.sciencedirect.com/science/article/abs/pii/S1043661820316108?via%3Dihub

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Education and communication are critical to effectively incorporating cannabis into cancer treatment

“Providers need to be better equipped to discuss medical cannabis with patients even if they are not willing to prescribe it. The oncology community would be well served to ensure that providers are aware of existing cannabis research and are able to incorporate it into their communications with patients instead of leaving patients to figure out medical cannabis on their own.”

https://pubmed.ncbi.nlm.nih.gov/32986251/

https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33204

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Cancer patients’ experiences with medicinal cannabis-related care

 “Background: Little is known about medical cannabis (MC)-related care for patients with cancer using MC.

Methods: Semistructured telephone interviews were conducted in a convenience sample of individuals (n = 24) with physician-confirmed oncologic diagnoses and state/district authorization to use MC (Arizona, California, Florida, Illinois, Massachusetts, Oregon, New York, and Washington, DC) from April 2017 to March 2019. Standard qualitative techniques were used to assess the degree of MC-related health care oversight, MC practices, and key information sources.

Results: Among 24 participants (median age, 57 years; range, 30-71 years; 16 women [67%]), MC certifications were typically issued by a professional new to a patient’s care after a brief, perfunctory consultation. Patients disclosed MCuse to their established medical teams but received little medical advice about whether and how to use MC. Patients with cancer used MC products as multipurpose symptom management and as cancer-directed therapy, sometimes in lieu of standard-of-care treatments. Personal experimentation, including methodical self-monitoring, was an important source of MC know-how. Absent formal advice from medical professionals, patients relied on nonmedical sources for MC information.

Conclusions: Patients with cancer used MC with minimal medical oversight. Most received MC certifications through brief meetings with unfamiliar professionals. Participants desired but were often unable to access high-quality clinical information about MC from their established medical teams. Because many patients are committed to using MC, a product sustained by a growing industry, medical providers should familiarize themselves with the existing data for MM and its limitations to address a poorly met clinical need.”

https://pubmed.ncbi.nlm.nih.gov/32986266/

“Notably, oncology patients reported using medical cannabis (MC) for symptom management and as cancer‐directed therapy, sometimes instead of traditional treatments.”

https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33202

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Activation of Cannabinoid Receptor 2 Prevents Colitis-Associated Colon Cancer through Myeloid Cell De-activation Upstream of IL-22 Production

iScience journal (@iScience_CP) | Twitter
” Here we show that delta-9-tetrahydrocannabinol (THC) attenuates colitis-associated colon cancer and colitis induced by anti-CD40.
 THC can prevent the development of colitis-associated colon cancer in mice.”

“Study reveals how cannabinoids may be useful to prevent colon cancer”   https://medicalxpress.com/news/2020-09-reveals-cannabinoids-colon-cancer.html

“Key cannabis chemical may help prevent colon cancer, researchers say”   https://www.heraldmailmedia.com/news/nation/key-cannabis-chemical-may-help-prevent-colon-cancer-researchers-say/article_7afd0a72-eead-57f0-a1d3-006be62b7469.html

“Treatment with a cannabinoid prevented the development of colon cancers in mice” https://www.news-medical.net/news/20200915/Treatment-with-a-cannabinoid-prevented-the-development-of-colon-cancers-in-mice.aspx

Figure thumbnail fx1

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Cannabis sativa L. Extracts can reverse drug resistance in colorectal carcinoma cells in vitro

Synergy“Multidrug resistance (MDR) to known chemotherapeutic agents is increasing while the development of new drugs is lacking behind. Combination therapies might increase the development of effective treatment.

Anticancer properties of C. sativa L. have been extensively studied against various cancer cell lines but research on its effectiveness on MDR in cancer is less documented.

Aim

To determine the potential resistant reversal of the cytostatic drug doxorubicin by C. sativa L. extracts through combination studies.

Method

The cytotoxic effect of the different C. sativa L. extracts was assessed against a panel of human colon cancer cells (HT-29, Caco-2, HCT-15, LS513) and normal colon cells (CCD-18Co) by MTT assay. Drug-extract combination studies were performed on HCT-15 and LS513 MDR cells.

Results

DCM: methanol- and H2O extracts moderately inhibited the growth in HCT-15 and LS513 cells (IC50: 20–100 μg/ml). DCM- and H2O extracts potently inhibited HT-29 cell growth. Higher concentrations (100 μg/ml) of the hexane- and DCM- extracts slightly stimulated growth in Caco-2 cells. All the C. sativa L. extracts were more cytotoxic towards the cancerous cells than towards the normal colon cells. Combination studies between doxorubicin and the C. sativa L. extracts revealed synergistic growth inhibitory effects (CI < 1). The sensitivity to doxorubicin increased in HCT-15 and LS513 cells by 2.08- to 74.07-fold and 2.21- to 300.7-fold, respectively, compared to verapamil which improved it by 1.41-fold and 0.05-fold, respectively.

Conclusion

C. sativa L. extracts possess direct selective cytotoxic effect on colon cells and have a potential to reverse doxorubicin resistance.”

https://www.sciencedirect.com/science/article/abs/pii/S2213713019300021

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