“The spread of breast cancer to distant sites is the major cause of death in breast cancer patients. Increasing evidence supports the role of the tumor microenvironment (TME) in breast cancers, and its pathologic assessment has become a diagnostic and therapeutic tool. In the TME, a bidirectional interplay between tumor and stromal cells occurs, both at the primary and metastatic site. Hundreds of molecules, including cytokines, chemokines, and growth factors, contribute to this fine interaction to promote tumor spreading.

Here, we investigated the effects of Rimonabant and Cannabidiol, known for their antitumor activity, on reprogramming the breast TME.

Both compounds directly affect the activity of several pathways involved in breast cancer progression. To mimic tumor-stroma interactions during breast-to-lung metastasis, we investigated the effect of the compounds on growth factor secretion from metastatic breast cancer cells and normal and activated lung fibroblasts.

In this setting, we demonstrated the anti-metastatic potential of the two compounds, and the membrane array analyses highlighted their ability to alter the release of factors involved in the autocrine and paracrine regulation of tumor proliferation, angiogenesis, and immune reprogramming.

The results enforce the antitumor potential of Rimonabant and Cannabidiol, providing a novel potential tool for breast cancer TME management.”

https://pubmed.ncbi.nlm.nih.gov/37686233/

https://www.mdpi.com/1422-0067/24/17/13427

“Tamoxifen may lead to bothersome side effects contributing to non-compliance and decreased quality of life.

Patients searching for relief are increasingly turning to cannabinoids such as CBD-oil. However, CBD-oil might affect tamoxifen pharmacokinetics (PK) through CYP2D6 inhibition. The aims of this open-label, single-arm study were (1) to determine the PK profile of tamoxifen when using CBD-oil, and (2) to subsequently investigate whether CBD-oil has a beneficial influence on side effects.

Study patients had to have steady-state endoxifen concentrations ≥16 nM (conservative threshold). PK sampling and side effect assessment was done at initiation of CBD-oil and 28 days thereafter. Bio-equivalence could be concluded if the 90% confidence interval (CI) for the difference in endoxifen AUC fell within the [-20%; +25%] interval. The effect of CBD-oil on side effects was evaluated using the FACT-ES questionnaire.

Endoxifen AUC decreased after CBD-oil by 12.6% (n = 15, 90% CI -18.7%, -6.1%) but remained within bio-equivalence boundaries. The endocrine sub-scale of the FACT-ES improved clinically relevant with 6.7 points (n = 26, p < 0.001) and health-related quality of life improved with 4.7 points after using CBD (95% CI + 1.8, +7.6).

We conclude that CBD-oil, if of good quality and with a dosage below 50 mg, does not have to be discouraged in patients using it for tamoxifen-related side effects.”

https://pubmed.ncbi.nlm.nih.gov/37543688/

“In conclusion, endoxifen levels remained within bio-equivalence boundaries when CBD-oil was used in combination with tamoxifen. Therefore, sublingual CBD-oil, if of good quality and not higher than the highest over-the-counter dose (<50 mg per day), does not have to be discouraged in patients using it as complementary medication. In addition, the use of CBD-oil in this single arm study resulted in a promising improvement in endocrine symptoms and quality of life, but the real effect of CBD-oil has yet to be proven in a placebo-controlled study that is currently being set up.”

https://www.nature.com/articles/s41523-023-00570-x

“The present study investigated the ability of Cannabis sativa leaves infusion (CSI) to modulate major metabolisms implicated in cancer cells survival, as well as to induce cell death in human breast cancer (MCF-7) cells. MCF-7 cell lines were treated with CSI for 48 h, doxorubicin served as the standard anticancer drug, while untreated MCF-7 cells served as the control. CSI caused 21.2% inhibition of cell growth at the highest dose. Liquid chromatography-mass spectroscopy (LC-MS) profiling of the control cells revealed the presence of carbohydrate, vitamins, oxidative, lipids, nucleotides, and amino acids metabolites. Treatment with CSI caused a 91% depletion of these metabolites, while concomitantly generating selenomethionine, l-cystine, deoxyadenosine triphosphate, cyclic AMP, selenocystathionine, inosine triphosphate, adenosine phosphosulfate, 5′-methylthioadenosine, uric acid, malonic semialdehyde, 2-methylguanosine, ganglioside GD2 and malonic acid. Metabolomics analysis via pathway enrichment of the metabolites revealed the activation of key metabolic pathways relevant to glucose, lipid, amino acid, vitamin, and nucleotide metabolisms. CSI caused a total inactivation of glucose, vitamin, and nucleotide metabolisms, while inactivating key lipid and amino acid metabolic pathways linked to cancer cell survival. Flow cytometry analysis revealed an induction of apoptosis and necrosis in MCF-7 cells treated with CSI. High-performance liquid chromatography (HPLC) analysis of CSI revealed the presence of cannabidiol, rutin, cinnamic acid, and ferulic. These results portray the antiproliferative potentials of CSI as an alternative therapy for the treatment and management of breast cancer as depicted by its modulation of glucose, lipid, amino acid, vitamin, and nucleotide metabolisms, while concomitantly inducing cell death in MCF-7 cells.”

https://pubmed.ncbi.nlm.nih.gov/37215911/

https://www.cell.com/heliyon/fulltext/S2405-8440(23)03363-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405844023033637%3Fshowall%3Dtrue

“Background: Estrogen receptor-positive (ER⁺) breast cancer is the most diagnosed subtype, with aromatase inhibitors (AIs) being one of the therapeutic drug types used in the clinic. However, endocrine resistance may develop after prolonged treatment, and different approaches, such as combining endocrine and targeted therapies, have been applied. Recently, we demonstrated that cannabidiol (CBD) induces anti-tumor actions in ER⁺ breast cancer cells by targeting aromatase and ERs. Considering this, we studied, in vitro, whether CBD when combined with AIs could improve their effectiveness.

Methods: MCF-7aro cells were used and the effects on cell viability and on the modulation of specific targets were investigated.

Results: CBD when combined with anastrozole (Ana) and letrozole (Let) caused no beneficial effect in comparison to the isolated AIs. In contrast, when combined with the AI exemestane (Exe), CBD potentiated its pro-cell death effects, abolished its estrogen-like effect, impaired ERα activation, and prevented its oncogenic role on the androgen receptor (AR). Moreover, this combination inhibited ERK_1/2 activation, promoting apoptosis. The study of the hormonal microenvironment suggests that this combination should not be applied in early stages of ER⁺ breast tumors.

Conclusions: Contrary to Ana and Let, this study highlights the potential benefits of combining CBD with Exe to improve breast cancer treatment and opens up the possibility of new therapeutic approaches comprising the use of cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/37173983/

“Cannabidiol (CBD) has demonstrated important anti-tumor effects on ER⁺ breast cancer cells. Considering this, our goal was to evaluate the effects of combining CBD with the AIs currently in use in the clinical context. Our results revealed that CBD may be particularly beneficial when combined with the AI exemestane (Exe), since it potentiates the anti-tumor effects of Exe through the modulation of cell death and specific targets, including ERα and androgen receptor (AR). This reinforces the beneficial potential of cannabinoids in breast cancer and points to the possibility of improving Exe effects through an adjuvant therapy with CBD.”

https://www.mdpi.com/2072-6694/15/9/2517

“Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer-related death among women worldwide. Somatostatin (SST) and Cannabinoids have an anti-proliferative and pro-apoptotic effect, but the mechanisms of their actions remain elusive.

In the present study, we have evaluated the effects of SST, Cannabidiol (CBD) alone or in combination on receptor expression, cell proliferation and apoptosis and related downstream signalling pathways in MDA-MB-231 and MCF-7 breast cancer cells.

The results presented here demonstrate the cell type and agonist-dependent changes in receptor expression at the cell membrane, inhibition of cell proliferation and increased apoptosis following treatment with SST and CBD alone and in combination. In comparison to MDA-MB-231 cells, MCF-7 cells treated with SST alone and in combination with CBD exhibited inhibition of phosphorylated Protein Kinase B (pAKT) and phosphorylated-Phosphoinositide 3-Kinase (pPI3K) expression. Importantly, inhibition of PI3K/AKT activation was accompanied by enhanced PTEN expression in MCF-7 cells.

These results highlight the possible interaction between SSTR and CBR subtypes with the implication in the modulation of receptor expression, cell viability and signal transduction pathways in a breast cancer cell type-dependent manner.”

https://pubmed.ncbi.nlm.nih.gov/36586156/

“Marijuana (or cannabis) is a source of large numbers of compounds known as phytocannabinoids, such as delta-9-tetrahydrocannabinol (Δ⁹-THC) and Cannabidiol (CBD) that have therapeutic implications in cancer, pain, inflammation and neurological diseases.”

https://www.sciencedirect.com/science/article/abs/pii/S0006291X22017442?via%3Dihub

“Epidermal growth factor receptor (EGFR) is a member of the ErbB family of proteins and are involved in downstream signal transduction, plays prominent roles in cell growth regulation, proliferation, and the differentiation of many cell types. They are correlated with the stage and severity of cancer. Therefore, EGFRs are targeted proteins for the design of new drugs to treat cancers that overexpress these proteins. Currently, several bioactive natural extracts are being studied for therapeutic purposes.

Cannabis has been reported in many studies to have beneficial medicinal effects, such as anti-inflammatory, analgesic, antibacterial, and anti-inflammatory effects, and antitumor activity. However, it is unclear whether cannabinoids reduce intracellular signaling by inhibiting tyrosine kinase phosphorylation. In this study, cannabinoids (CBD, CBG, and CBN) were simulated for binding to the EGFR-intracellular domain to evaluate the binding energy and binding mode based on molecular docking simulation.

The results showed that the binding site was almost always located at the kinase active site. In addition, the compounds were tested for binding affinity and demonstrated their ability to inhibit kinase enzymes. Furthermore, the compounds potently inhibited cellular survival and apoptosis induction in either of the EGFR-overexpressing cell lines.”

https://pubmed.ncbi.nlm.nih.gov/36568260/

“Cannabinoids reduced cell viability in EGFR-positive cells A431 and A549 by decreasing the tyrosine-kinase phosphorylation activity of EGFR.•

In silico analysis shows that cannabinoids bind to the active site of the EGFR-tyrosine kinase by the hydrophobic interaction and hydrogen bonding.•

CBD and CBG significantly induce cancer cells apoptosis in EGFR-positive cell A431.•

The consistent findings suggested that CBD and CBG could be developed as natural tumor-targeting agents for EGFR-positive cancers.

These findings demonstrate that the cannabinoids could be transformed into unique natural compounds for use in the development of anti-EGFR-positive cancer therapies.”

https://www.sciencedirect.com/science/article/pii/S2590257122000529?via%3Dihub