Category Archives: Breast Cancer

Combined CB2 Receptor Agonist and Photodynamic Therapy Synergistically Inhibit Tumor Growth in Triple Negative Breast Cancer.

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Photodiagnosis and Photodynamic Therapy

“Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because compared with other types of breast cancer, it is more aggressive, diagnosed at later stage and more likely to develop recurrence.

Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life.

Here we report a new combinatory therapy strategy involving cannabinoid-based medicine and photodynamic therapy (PDT) for the treatment of TNBC.

This combinatory therapy targets two proteins upregulated in TNBC: the cannabinoid CB2 receptor (CB2R, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the combined CB2R agonist and TSPO-PDT treatment resulted in synergistic inhibition in TNBC cell and tumor growth.

This combinatory therapy approach provides new opportunities to treat TNBC with high efficacy. In addition, this study provides new evidence on the therapeutic potential of CB2R agonists for cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/30240926

https://www.sciencedirect.com/science/article/pii/S1572100018301571?via%3Dihub

Cannabidiol (CBD) Is a Novel Inhibitor for Exosome and Microvesicle (EMV) Release in Cancer.

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“Exosomes and microvesicles (EMV) are lipid bilayer-enclosed structures, released by cells and involved in intercellular communication through transfer of proteins and genetic material. EMV release is also associated with various pathologies, including cancer, where increased EMV release is amongst other associated with chemo-resistance and active transfer of pro-oncogenic factors.

Recent studies show that EMV-inhibiting agents can sensitize cancer cells to chemotherapeutic agents and reduce cancer growth in vivo.

Cannabidiol (CBD), a phytocannabinoid derived from Cannabis sativa, has anti-inflammatory and anti-oxidant properties, and displays anti-proliferative activity.

Here we report a novel role for CBD as a potent inhibitor of EMV release from three cancer cell lines: prostate cancer (PC3), hepatocellular carcinoma (HEPG2) and breast adenocarcinoma (MDA-MB-231).

CBD significantly reduced exosome release in all three cancer cell lines, and also significantly, albeit more variably, inhibited microvesicle release.

The EMV modulating effects of CBD were found to be dose dependent (1 and 5 μM) and cancer cell type specific. Moreover, we provide evidence that this may be associated with changes in mitochondrial function, including modulation of STAT3 and prohibitin expression, and that CBD can be used to sensitize cancer cells to chemotherapy.

We suggest that the known anti-cancer effects of CBD may partly be due to the regulatory effects on EMV biogenesis, and thus CBD poses as a novel and safe modulator of EMV-mediated pathological events.”

https://www.ncbi.nlm.nih.gov/pubmed/30150937

https://www.frontiersin.org/articles/10.3389/fphar.2018.00889/full

Anti-tumoural actions of cannabinoids.

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“The endocannabinoid system has emerged as a considerable target for the treatment of diverse diseases.

In addition to the well-established palliative effects of cannabinoids in cancer therapy, phytocannabinoids, synthetic cannabinoid compounds as well as inhibitors of endocannabinoid degradation have attracted attention as possible systemic anticancer drugs.

As a matter of fact, accumulating data from preclinical studies suggest cannabinoids elicit effects on different levels of cancer progression, comprising inhibition of proliferation, neovascularisation, invasion and chemoresistance, induction of apoptosis and autophagy as well as enhancement of tumour immune surveillance.

Although the clinical use of cannabinoid receptor ligands is limited by their psychoactivity, nonpsychoactive compounds, such as cannabidiol, have gained attention due to preclinically established anticancer properties and a favourable risk-to-benefit profile.

Thus, cannabinoids may complement the currently used collection of chemotherapeutics, as a broadly diversified option for cancer treatment, while counteracting some of their severe side effects.” https://www.ncbi.nlm.nih.gov/pubmed/30019449

“During the last few decades, a large body of evidence has accumulated to suggest endocannabinoids, phytocannabinoids and synthetic cannabinoids exert an inhibitory effect on cancer growth via blockade of cell proliferation and induction of apoptosis. Some studies support the hypothesis that cannabinoids may enhance immune responses against the progressive growth and spread of tumours.”  https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14426#bph14426-fig-0001
“Previous research has shown that cannabinoids can help lessen side effects of anti-cancer therapies. Now a new British Journal of Pharmacology review has examined their potential for the direct treatment of cancer. Studies have shown that cannabinoids may stop cancer cells from dividing and invading normal tissue, and they may block the blood supply to tumors. Some studies also indicate that cannabinoids may enhance the body’s immune response against the growth and spread of tumors.” https://www.eurasiareview.com/19072018-cannabinoids-may-have-a-vast-array-of-anti-cancer-effects/
“Cannabinoids may have a vast array of anti-cancer effects” https://www.sciencedaily.com/releases/2018/07/180718082143.htm

“Cannabinoids may have a vast array of anti-cancer effects”  https://www.eurekalert.org/pub_releases/2018-07/w-cmh071718.php

“Marijuana may help fight cancer” https://nypost.com/2018/07/18/marijuana-may-help-fight-cancer/

“Cannabis stops cancer spreading and boosts immune system, say scientists. Studies show cannabinoids can stop cancer cells from dividing and spreading, and blocks blood supply to tumours” https://www.plymouthherald.co.uk/news/health/cannabis-can-cure-cancer-proof-1803485
“Cannabis stops cancer spreading and boosts immune system, say scientists. Cannabis can act as a treatment for cancer and boost the immune system, claims a new study.” https://www.devonlive.com/news/health/cannabis-can-cure-cancer-proof-1803485
“Cannabis stops cancer spreading and boosts immune system, say scientists. Cannabis can act as a treatment for cancer and boost the immune system, claims a new study.” https://www.cornwalllive.com/news/uk-world-news/cannabis-can-cure-cancer-proof-1803485
“Cannabis ‘can act as a treatment for cancer’. Cannabis can enhance the immune system and act as a treatment for cancer, claims a new study. Scientists at Rostock University Medical Centre in Germany claimed the benefits following a review of more than 100 studies.” https://www.thelondoneconomic.com/news/cannabis-can-act-as-a-treatment-for-cancer/19/07/

Novel mechanism of cannabidiol-induced apoptosis in breast cancer cell lines.

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The Breast Home

“Studies have emphasized an antineoplastic effect of the non-psychoactive, phyto-cannabinoid, Cannabidiol (CBD). However, the molecular mechanism underlying its antitumor activity is not fully elucidated.

Herein, we have examined the effect of CBD on two different human breast cancer cell lines: the ER-positive, well differentiated, T-47D and the triple negative, poor differentiated, MDA-MB-231 cells.

In both cell lines, CBD inhibited cell survival and induced apoptosis in a dose dependent manner as observed by MTT assay, morphological changes, DNA fragmentation and ELISA apoptosis assay. CBD-induced apoptosis was accompanied by down-regulation of mTOR, cyclin D1 and up-regulation and localization of PPARγ protein expression in the nuclei and cytoplasmic of the tested cells.

The results suggest that CBD treatment induces an interplay among PPARγ, mTOR and cyclin D1 in favor of apoptosis induction in both ER-positive and triple negative breast cancer cells, proposing CBD as a useful treatment for different breast cancer subtypes.”

https://www.ncbi.nlm.nih.gov/pubmed/30007266
https://www.thebreastonline.com/article/S0960-9776(18)30121-8/fulltext
“Programmed Cell Death (Apoptosis)” http://www.ncbi.nlm.nih.gov/books/NBK26873/

Appraising the “entourage effect”: antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer.

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“Breast cancer is the second leading cause of death among women. Although early diagnosis and development of new treatments have improved their prognosis, many patients present innate or acquired resistance to current therapies. New therapeutic approaches are therefore warranted for the management of this disease.

Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer. Most of these studies have been conducted with pure compounds, mainly Δ9-tetrahydrocannabinol (THC).

The cannabis plant, however, produces hundreds of other compounds with their own therapeutic potential and the capability to induce synergic responses when combined, the so-called “entourage effect”.

Here, we compared the antitumor efficacy of pure THC with that of a botanical drug preparation (BDP). The BDP was more potent than pure THC in producing antitumor responses in cell culture and animal models of ER+/PR+, HER2+ and triple-negative breast cancer. This increased potency was not due to the presence of the 5 most abundant terpenes in the preparation.

While pure THC acted by activating cannabinoid CB2 receptors and generating reactive oxygen species, the BDP modulated different targets and mechanisms of action. The combination of cannabinoids with estrogen receptor- or HER2-targeted therapies (tamoxifen and lapatinib, respectively) or with cisplatin, produced additive antiproliferative responses in cell cultures. Combinations of these treatments in vivo showed no interactions, either positive or negative.

Together, our results suggest that standardized cannabis drug preparations, rather than pure cannabinoids, could be considered as part of the therapeutic armamentarium to manage breast cancer.”

 https://www.ncbi.nlm.nih.gov/pubmed/29940172

A peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain.

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“Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain.

Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients’ quality of life.

In contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP.

Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP.

Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects.

Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP.”

 https://www.ncbi.nlm.nih.gov/pubmed/29781960
https://insights.ovid.com/crossref?an=00006396-900000000-98957

INSIGHT ON THE IMPACT OF ENDOCANNABINOID SYSTEM IN CANCER: A REVIEW.

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“In the last decades, the endocannabinoid system has attracted a great interest in medicine and cancer disease is probably one of its most promising therapeutic areas.

On the one hand, endocannabinoid system expression has been found altered in numerous types of tumours compared to healthy tissue, and this aberrant expression has been related to cancer prognosis and disease outcome, suggesting a role of this system in tumour growth and progression that depends on cancer type.

On the other hand, it has been reported that cannabinoids exert an anticancer activity by inhibiting the proliferation, migration and/or invasion of cancer cells; and also tumour angiogenesis.

The endocannabinoid system may be considered as a new therapeutic target, although further studies to fully establish the effect of cannabinoids on tumour progression remain necessary.”

https://www.ncbi.nlm.nih.gov/pubmed/29663308

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14331

Anti-invasion Effects of Cannabinoids Agonist and Antagonist on Human Breast Cancer Stem Cells.

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“Studies show that cancer cell invasion or metastasis is the primary cause of death in malignancies including breast cancer.

The existence of cancer stem cells (CSCs) in breast cancer may account for tumor initiation, progression, and metastasis.

Recent studies have reported different effects of cannabinoids on cancer cells via CB1 and CB2 cannabinoid receptors.

In the present study, the effects of ACEA (a selective CB1 receptor agonist) and AM251 (a selective CB1 antagonist) on CSCs and their parental cells were investigated.

It was observed that ACEA decreased CD44+/CD24-/low/ESA+ cancer stem cell invasiveness.

Since one of the main cancer recurrence factors is anti-cancer drugs fail to inhibit CSC population, this observation would be useful for cancer treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/29552056

“Our results indicate that cannabinoids may interfere with invasive cancer stem cells in benefit of cancer eradication. In summary, our results clarified that cannabinoid receptor agonist possesses anti-invasion potential in both main population and breast cancer stem cells. Considering that most anti-cancer drugs do not eradicate stem cells and only target main population cells, the results disclosed here can be used for prevention of cancer recurrence.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843309/

Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death.

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“Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells.

Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells.

Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death.

Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance.

Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD.

Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD.

The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/24309936

“The non-psychoactive plant cannabinoid, cannabidiol (CBD), alone has strong anti-inflammatory and immunosuppressive effects in diverse animal models of disease such as diabetes, cancer, rheumatoid arthritis and multiple sclerosis. In addition, CBD has been reported to have anxiolytic, antiemetic and antipsychotic effects. Moreover, CBD has been shown to possess antitumor activity in human breast carcinoma and to effectively reduce primary tumor mass, as well as size and number of lung metastasis in preclinical animal models of breast cancer.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877544/

“In summary, in this study we have identified VDAC1 as a new molecular target for CBD. Our study suggests that CBD-induced cell death may occur through the inhibition of VDAC1 conductance and that this interaction may be responsible for the anticancer and immunosuppressive properties of CBD.”

https://www.nature.com/articles/cddis2013471

“Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-CancerTherapeutics.” https://www.ncbi.nlm.nih.gov/pubmed/28824871

“Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target.”  https://www.ncbi.nlm.nih.gov/pubmed/25448878

Cannabidiol Induces Cytotoxicity and Cell Death via Apoptotic Pathway in Cancer Cell Lines

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“In view of obtaining potential anticancer compounds, we studied the inhibitory activity and the cytotoxic effects of a candidate compound in cancer cells. The cytotoxic effects of cannabidiol (CBD) in vitro were evaluated in NIH3T3 fibroblasts, B16 melanoma cells, A549 lung cancer cells, MDA-MB-231 breast cancer cells, Lenca kidney cells and SNU-C4 colon cancer cells.
The inhibitory activity of CBD was increased in all cancer cells and showed especially strong increment in breast cancer cells. The cytotoxicity of CBD increased in a dose- and time-dependent manner with growth inhibition in all cancer cell lines.
Therefore these results suggest that CBD has a possibility of anticancer agents and anticancer effects against cancer cells by modulation of apoptotic pathway in the range of 5-80 μM concentration.”
https://www.researchgate.net/publication/247915772_Cannabidiol_Induces_Cytotoxicity_and_Cell_Death_via_Apoptotic_Pathway_in_Cancer_Cell_Lines
http://www.biomolther.org/journal/view.html?uid=25&vmd=Full