Cannabinoids as anticancer therapeutic agents.

Posted on April 7, 2020 by David

Cell Cycle Journal are Co-Sponsoring #ACCM15 – The Cell Division Lab “The recent announcement of marijuana legalization in Canada spiked many discussions about potential health benefits of Cannabis sativa. Cannabinoids are active chemical compounds produced by cannabis, and their numerous effects on the human body are primarily exerted through interactions with cannabinoid receptor types 1 (CB₁) and 2 (CB₂). Cannabinoids are broadly classified as endo-, phyto-, and synthetic cannabinoids. In this review, we will describe the activity of cannabinoids on the cellular level, comprehensively summarize the activity of all groups of cannabinoids on various cancers and propose several potential mechanisms of action of cannabinoids on cancer cells.”

https://www.ncbi.nlm.nih.gov/pubmed/32249682

“Endocannabinoids and phytocannabinoids can be used for cancer therapy. Cannabis extracts have stronger anti-tumor capacity than single cannabinoids. Combination of several cannabinoids may have more potent effect on cancer.”

https://www.tandfonline.com/doi/abs/10.1080/15384101.2020.1742952?journalCode=kccy20

CBD Reverts the Mesenchymal Invasive Phenotype of Breast Cancer Cells Induced by the Inflammatory Cytokine IL-1β.

Posted on April 5, 2020 by David

“Cannabidiol (CBD) has been used to treat a variety of cancers and inflammatory conditions with controversial results. In previous work, we have shown that breast cancer MCF-7 cells, selected by their response to inflammatory IL-1β cytokine, acquire a malignant phenotype (6D cells) through an epithelial-mesenchymal transition (EMT).

We evaluated CBD as a potential inhibitor of this transition and inducer of reversion to a non-invasive phenotype. It decreased 6D cell viability, downregulating expression of receptor CB1. The CBD blocked migration and progression of the IL-1β-induced signaling pathway IL-1β/IL-1RI/β-catenin, the driver of EMT.

Cannabidiol reestablished the epithelial organization lost by dispersion of the cells and re-localized E-cadherin and β-catenin at the adherens junctions. It also prevented β-catenin nuclear translocation and decreased over-expression of genes for ∆Np63α, BIRC3, and ID1 proteins, induced by IL-1β for acquisition of malignant features.

Cannabidiol inhibited the protein kinase B (AKT) activation, a crucial effector in the IL-1β/IL-1RI/β-catenin pathway, indicating that at this point there is crosstalk between IL-1β and CBD signaling which results in phenotype reversion.

Our 6D cell system allowed step-by-step analysis of the phenotype transition and better understanding of mechanisms by which CBD blocks and reverts the effects of inflammatory IL-1β in the EMT.”

https://www.ncbi.nlm.nih.gov/pubmed/32244518

https://www.mdpi.com/1422-0067/21/7/2429

Cannabidiolic acid dampens the expression of cyclooxygenase-2 in MDA-MB-231 breast cancer cells: Possible implication of the peroxisome proliferator-activated receptor β/δ abrogation.

Posted on April 3, 2020 by David

The Journal of Toxicological Sciences “A growing body of experimental evidence strongly suggests that cannabidiolic acid (CBDA), a major component of the fiber-type cannabis plant, exerts a variety of biological activities.

We have reported that CBDA can abrogate cyclooxygenase-2 (COX-2) expression and its enzymatic activity. It is established that aberrant expression of COX-2 correlates with the degree of malignancy in breast cancer.

Although the reduction of COX-2 expression by CBDA offers an attractive medicinal application, the molecular mechanisms underlying these effects have not fully been established.

It has been reported that COX-2 expression is positively controlled by peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in some cancerous cells, although there is “no” modulatory element for PPARβ/δ on the COX-2 promoter. No previous studies have examined whether an interaction between PPARβ/δ-mediated signaling and COX-2 expression exists in MDA-MB-231 cells.

We confirmed, for the first time, that COX-2 expression is positively modulated by PPARβ/δ-mediated signaling in MDA-MB-231 cells. CBDA inhibits PPARβ/δ-mediated transcriptional activation stimulated by the PPARβ/δ-specific agonist, GW501516. Furthermore, the disappearance of cellular actin stress fibers, a hallmark of PPARβ/δ and COX-2 pathway activation, as evoked by the GW501516, was effectively reversed by CBDA. Activator protein-1 (AP-1)-driven transcriptional activity directly involved in the regulation of COX-2 was abrogated by the PPARβ/δ-specific inverse agonists (GSK0660/ST-247). Thus, it is implicated that there is positive interaction between PPARβ/δ and AP-1 in regulation of COX-2.

These data support the concept that CBDA is a functional down-regulator of COX-2 through the abrogation of PPARβ/δ-related signaling, at least in part, in MDA-MB-231 cells.”

https://www.ncbi.nlm.nih.gov/pubmed/32238697

https://www.jstage.jst.go.jp/article/jts/45/4/45_227/_article

n-3 Polyunsaturated Fatty Acid Amides: New Avenues in the Prevention and Treatment of Breast Cancer.

Posted on April 3, 2020 by David

“Over the last decades a renewed interest in n-3 very long polyunsaturated fatty acids (PUFAs), derived mainly from fish oils in the human diet, has been observed because of their potential effects against cancer diseases, including breast carcinoma. These n-3 PUFAs mainly consist of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that, alone or in combination with anticancer agents, induce cell cycle arrest, autophagy, apoptosis, and tumor growth inhibition. A large number of molecular targets of n-3 PUFAs have been identified and multiple mechanisms appear to underlie their antineoplastic activities. Evidence exists that EPA and DHA also elicit anticancer effects by the conversion to their corresponding ethanolamide derivatives in cancer cells, by binding and activation of different receptors and distinct signaling pathways. Other conjugates with serotonin or dopamine have been found to exert anti-inflammatory activities in breast tumor microenvironment, indicating the importance of these compounds as modulators of tumor epithelial/stroma interplay. The objective of this review is to provide a general overview and an update of the current n-3 PUFA derivative research and to highlight intriguing aspects of the potential therapeutic benefits of these low-toxicity compounds in breast cancer treatment and care.”

https://www.ncbi.nlm.nih.gov/pubmed/32224850

https://www.mdpi.com/1422-0067/21/7/2279

“Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion.” https://www.ncbi.nlm.nih.gov/pubmed/31679810

Insight of Druggable Cannabinoids against Estrogen Receptor β in Breast Cancer.

Posted on March 3, 2020 by David

Publication Cover

“Breast cancer (BC) is the second most prevalent cancer worldwide.

Estrogen receptor beta (ERβ) is an essential protein of breast cells to suppress estrogen induced uncontrolled proliferation. Thus small molecules that can modulate and enhance ERβ expression would be an effective agent to suppress BC development.

Studies showed that cannabinoid (CB), specifically Delta-9-tetrahydrocannabinol (Del9THC), can increase the expression of ERβ and inhibits BC cell proliferation.

In this study, less psychoactive and structurally similar analogues of Del9THC were chosen as drug candidates and ERβ was targeted as a therapeutic receptor. Delta-8-tetrahydrocannabinol (Del8THC) and Delta-4-Isotetrahydrocannabinol (Del4isoTHC) were the drug candidates selected on the basis of literature reports, Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties, medicinal chemistry profile and physicochemical features.

Molecular docking simulations were carried out to determine ligand receptor interactions and binding affinity based on free binding energy. To get a better drug, the structural modification was done on Del8THC and generated a new CB analogue called Cannabinoid A.

Finally, molecular interaction analysis revealed that two CBs and one of their analogue interact with the active site residues of ERβ. Therefore, this study revealed a new way to discover novel drug(s) for BC patients.”

https://www.ncbi.nlm.nih.gov/pubmed/32116130

https://www.tandfonline.com/doi/abs/10.1080/07391102.2020.1737233?journalCode=tbsd20

Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment.

Posted on March 3, 2020 by David

“Breast cancer (BC) is the most common cancer in women worldwide. Approximately 70-80% of BCs express estrogen receptors (ER), which predict the response to endocrine therapy (ET), and are therefore hormone receptor-positive (HR+).

Endogenous cannabinoids together with cannabinoid receptor 1 and 2 (CB1, CB2) constitute the basis of the endocannabinoid system.

Interactions of cannabinoids with hypothalamic-pituitary-gonadal axis hormones are well documented, and two studies found a positive correlation between peak plasma endogenous cannabinoid anandamide with peak plasma 17β-estradiol, luteinizing hormone and follicle-stimulating hormone levels at ovulation in healthy premenopausal women. Do cannabinoids have an effect on HR+ BC? In this paper we review known and possible interactions between cannabinoids and specific HR+ BC treatments.

In preclinical studies, CB1 and CB2 agonists (i.e., anandamide, THC) have been shown to inhibit the proliferation of ER positive BC cell lines.

There is less evidence for antitumor cannabinoid action in HR+ BC in animal models and there are no clinical trials exploring the effects of cannabinoids on HR+ BC treatment outcomes. Two studies have shown that tamoxifen and several other selective estrogen receptor modulators (SERM) can act as inverse agonists on CB1 and CB2, an interaction with possible clinical consequences. In addition, cannabinoid action could interact with other commonly used endocrine and targeted therapies used in the treatment of HR+ BC.”

https://www.ncbi.nlm.nih.gov/pubmed/32106399

https://www.mdpi.com/2072-6694/12/3/525

The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain.

Posted on February 17, 2020 by David

Journal of Pharmacology and Experimental Therapeutics: 372 (3) “Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis are long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects.

In our study we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer induced bone pain (CIBP). Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activate CB1 and CB2 receptors inhibiting inflammation and pain.

Together, these data support the application for MJN110 as a novel therapeutic for cancer induced bone pain.

SIGNIFICANCE STATEMENT: Current standard of care for metastatic breast cancer pain is opioid-based therapies with adjunctive chemotherapy, which have highly addictive and other deleterious side effects. The need for effective, non-opioid based therapies is essential and harnessing the endogenous cannabinoid system is proving to be a new target to treat various types of pain conditions. We present a novel drug targeting the endogenous cannabinoid system that is effective at reducing pain in a mouse model of metastatic breast cancer to bone.”

https://www.ncbi.nlm.nih.gov/pubmed/32054717

http://jpet.aspetjournals.org/content/early/2020/02/13/jpet.119.262337

The Endocannabinoid System: A Target for Cancer Treatment.

Posted on January 26, 2020 by David

“In recent years, the endocannabinoid system has received great interest as a potential therapeutic target in numerous pathological conditions.

Cannabinoids have shown an anticancer potential by modulating several pathways involved in cell growth, differentiation, migration, and angiogenesis.

However, the therapeutic efficacy of cannabinoids is limited to the treatment of chemotherapy-induced symptoms or cancer pain, but their use as anticancer drugs in chemotherapeutic protocols requires further investigation.

In this paper, we reviewed the role of cannabinoids in the modulation of signaling mechanisms implicated in tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/31979368

https://www.mdpi.com/1422-0067/21/3/747

“In addition to the symptomatic therapy of cancer patients, the antitumor effects of cannabinoids (whether in monotherapy or in combination with other cancer therapies) have promising potential in the treatment of cancer patients.” https://www.ncbi.nlm.nih.gov/pubmed/31950844
“In addition to the well-known palliative effects of cannabinoids on some cancer-associated symptoms, a large body of evidence shows that these molecules can decrease tumour growth in animal models of cancer. In addition, cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals. Thus, numerous studies have provided evidence that thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/

“Antitumour actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/30019449

“The endocannabinoid system as a target for the development of new drugs for cancer therapy” https://www.ncbi.nlm.nih.gov/pubmed/12723496

“Cannabinoids as Anticancer Drugs.” https://www.ncbi.nlm.nih.gov/pubmed/28826542

http://www.thctotalhealthcare.com/category/cancer/

CBD loaded microparticles as a potential formulation to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer.

Posted on December 8, 2019 by David

International Journal of Pharmaceutics “Cannabidiol (CBD) has emerged as a potential agent for breast cancer management.

In this work, the potential use of cannabidiol in solution (CBD_sol) and encapsulated in polymeric microparticles when combined with paclitaxel (PTX) and doxorubicin (DOX) in breast cancer treatment has been evaluated for the first time using MCF-7 and MDA-MB-231 cells. CBD_sol, previously administered at suboptimal concentrations (cell death <10%), enhanced the PTX and DOX effect in both breast cancer cells.

The co-administration of CBD_sol and PTX or DOX showed a synergistic effect. PLGA-502 was selected as the most suitable polymer to develop CBD-loaded microparticles. The developed formulation (CBD-Mps) was effective as monotherapy, showing extended antiproliferative activity for at least 10 days, and when combined with PTX or DOX.

In fact, the use of CBD-Mps allows the combination of both, pre and co-administration strategies, with a single administration, also showing a significant increase in PTX and DOX antiproliferative activity. Finally, the anticancer effect of both CBD_sol and CBD-Mps as monotherapy or in combination with PTX was also confirmed in ovo, usingMDA-MB-231-derived tumours.

This data evidences the promising inclusion of CBD in conventional breast cancer chemotherapy and the use of CBD-Mps for the extended release of this cannabinoid, optimising the effect of the chemotherapeutic agents.”

https://www.ncbi.nlm.nih.gov/pubmed/31811927

https://www.sciencedirect.com/science/article/pii/S0378517319309615?via%3Dihub

Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion.

Posted on November 5, 2019 by David

“The anticancer effects of the omega-3 long chain polyunsaturated fatty acids (LCPUFA), EPA and DHA may be due, at least in part, to conversion to their respective endocannabinoid derivatives, eicosapentaenoyl-ethanolamine (EPEA) and docosahexaenoyl-ethanolamine (DHEA).

Here, the effects of EPEA and DHEA and their parent compounds, EPA and DHA, on breast cancer (BC) cell function was examined. EPEA and DHEA exhibited greater anti-cancer effects than EPA and DHA in two BC cells (MCF-7 and MDA-MB-231) whilst displaying no effect in non-malignant breast cells (MCF-10a).

Both BC lines expressed CB_1/2 receptors that were responsible, at least partly, for the observed anti-proliferative effects of the omega-3 endocannabinoids as determined by receptor antagonism studies. Additionally, major signalling mechanisms elicited by these CB ligands included altered phosphorylation of p38-MAPK, JNK, and ERK proteins.

Both LCPUFAs and their endocannabinoids attenuated the expression of signal proteins in BC cells, albeit to different extents depending on cell type and lipid effectors. These signal proteins are implicated in apoptosis and attenuation of BC cell migration and invasiveness.

Furthermore, only DHA reduced in vitro MDA-MB-231 migration whereas both LCPUFAs and their endocannabinoids significantly inhibited invasiveness. This finding was consistent with reduced integrin β3 expression observed with all treatments and reduced MMP-1 and VEGF with DHA treatment.

Attenuation of cell viability, migration and invasion of malignant cells indicates a potential adjunct nutritional therapeutic use of these LCPUFAs and/or their endocannabinoids in treatment of breast cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/31679810

https://www.plefa.com/article/S0952-3278(19)30112-7/fulltext