High Expression of Cannabinoid Receptor 2 on Cytokine-Induced Killer Cells and Multiple Myeloma Cells

ijms-logo“Multiple myeloma (MM) is characterized by aberrant bone marrow plasma cell (PC) proliferation and is one of the most common hematological malignancies. The potential effect of cannabinoids on the immune system and hematological malignancies has been poorly characterized.

Cannabidiol (CBD) may be used to treat various diseases. CBD is known to exert immunomodulatory effects through the activation of cannabinoid receptor 2 (CB2), which is expressed in high levels in the hematopoietic system.

Cytokine-induced killer (CIK) cells are a heterogeneous population of polyclonal T lymphocytes obtained via ex vivo sequential incubation of peripheral blood mononuclear cells (PBMCs) with interferon-γ (IFN-γ), anti CD3 monoclonal antibody, and IL-2. They are characterized by the expression of CD3+ and CD56+, which are surface markers common to T lymphocytes and natural killer (NK) cells. CIK cells are mainly used in hematological patients who suffer relapse after allogeneic transplantation.

Here, we investigated their antitumor effect in combination with pure cannabidiol in KMS-12 MM cells by lactate dehydrogenase LDH cytotoxicity assay, CCK-8 assay, and flow cytometry analysis. The surface and intracellular CB2 expressions on CIK cells and on KMS-12 and U-266 MM cell lines were also detected by flow cytometry.

Our findings confirm that the CB2 receptor is highly expressed on CIK cells as well as on MM cells. CBD was able to decrease the viability of tumor cells and can have a protective role for CIK cells. It also inhibits the cytotoxic activity of CIKs against MM at high concentrations, so in view of a clinical perspective, it has to be considered that the lower concentration of 1 µM can be used in combination with CIK cells. Further studies will be required to address the mechanism of CBD modulation of CIK cells in more detail.”

https://pubmed.ncbi.nlm.nih.gov/32471216/

https://www.mdpi.com/1422-0067/21/11/3800

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Inhibitor of Differentiation 1 (Id1) in Cancer and Cancer Therapy.

International Journal of Medical Sciences“The inhibitor of DNA binding (Id) proteins are regulators of cell cycle and cell differentiation. Of all Id family proteins, Id1 is mostly linked to tumorigenesis, cellular senescence as well as cell proliferation and survival.

Overall, Id1 represent a promising target of anti-tumor therapeutics based on its potent promotion effect to cancer. Numerous drugs were found exerting their anti-tumor function through Id1-related signaling pathways, such as fucoidan, berberine, tetramethylpyrazine, crizotinib, cannabidiol and vinblastine.”

https://www.ncbi.nlm.nih.gov/pubmed/32410828

“Id1 is a promising target of anti-tumor treatment as many compounds exert anti-tumor properties by mediating Id1-related pathways.”

https://www.medsci.org/v17p0995.htm

“Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness. Moreover, reducing Id-1 expression with cannabinoids could also provide a therapeutic strategy for the treatment of additional aggressive cancers because Id-1 expression was found to be up-regulated during the progression of almost all types of solid tumors investigated.”

https://mct.aacrjournals.org/content/6/11/2921

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PLGA Nanoparticles for the Intraperitoneal Administration of CBD in the Treatment of Ovarian Cancer: In Vitro and In Ovo Assessment.

pharmaceutics-logo“The intraperitoneal administration of chemotherapeutics has emerged as a potential route in ovarian cancer treatment. Nanoparticles as carriers for these agents could be interesting by increasing the retention of chemotherapeutics within the peritoneal cavity. Moreover, nanoparticles could be internalised by cancer cells and let the drug release near the biological target, which could increase the anticancer efficacy.

Cannabidiol (CBD), the main nonpsychotropic cannabinoid, appears as a potential anticancer drug. The aim of this work was to develop polymer nanoparticles as CBD carriers capable of being internalised by ovarian cancer cells.

The drug-loaded nanoparticles (CBD-NPs) exhibited a spherical shape, a particle size around 240 nm and a negative zeta potential (-16.6 ± 1.2 mV). The encapsulation efficiency was high, with values above 95%. A controlled CBD release for 96 h was achieved. Nanoparticle internalisation in SKOV-3 epithelial ovarian cancer cells mainly occurred between 2 and 4 h of incubation. CBD antiproliferative activity in ovarian cancer cells was preserved after encapsulation. In fact, CBD-NPs showed a lower IC50 values than CBD in solution. Both CBD in solution and CBD-NPs induced the expression of PARP, indicating the onset of apoptosis. In SKOV-3-derived tumours formed in the chick embryo model, a slightly higher-although not statistically significant-tumour growth inhibition was observed with CBD-NPs compared to CBD in solution.

To sum up, poly-lactic-co-glycolic acid (PLGA) nanoparticles could be a good strategy to deliver CBD intraperitoneally for ovarian cancer treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/32397428

https://www.mdpi.com/1999-4923/12/5/439

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Possible Enhancement of Photodynamic Therapy (PDT) Colorectal Cancer Treatment when Combined with Cannabidiol.

“Colorectal cancer (CRC) has a high mortality rate and is one of the most difficult diseases to manage due to tumour resistance and metastasis. The treatment of choice for CRC is reliant on the phase and time of diagnosis. Despite several conventional treatments available to treat CRC (surgical excision, chemo-, radiation- and immune-therapy), resistance is a major challenge, especially if it has metastasized. Additionally, these treatments often cause unwanted adverse side effects and so it remains imperative to investigate, alternative combination therapies.

Photodynamic Therapy (PDT) is a promising treatment modality for the primary treatment of CRC, since it is non-invasive, has few side effects and selectively damages only cancerous tissues, leaving adjacent healthy structures intact. PDT involves three fundamentals: a Photosensitizer (PS) drug localized in tumour tissues, oxygen and light. Upon PS excitation using a specific wavelength of light, an energy transfer cascade occurs, that ultimately yields cytotoxic species, which in turn induces cell death.

Cannabidiol (CBD) is a cannabinoid compound derived from the Cannabis sativa plant, which is found to exert anticancer effects on CRC through different pathways, inducing apoptosis and so inhibits tumour metastasis and secondary spread.

This review paper highlights current conventional treatment modalities for CRC and their limitations, as well as discusses the necessitation for further investigation into unconventional active nanoparticle targeting PDT treatments for enhanced primary CRC treatment. This can be administered in combination with CBD, to prevent CRC secondary spread and so enhance the synergistic efficacy of CRC treatment outcomes, with less side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/32294046

http://www.eurekaselect.com/180902/article

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Synergistic cytotoxic activity of cannabinoids from cannabis sativa against cutaneous T-cell lymphoma (CTCL) in-vitro and ex-vivo.

 Peer-reviewed Oncology & Cancer Research Journal | Oncotarget“Cannabis sativa produces hundreds of phytocannabinoids and terpenes.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), characterized by patches, plaques and tumors. Sézary is a leukemic stage of CTCL presenting with erythroderma and the presence of neoplastic Sézary T-cells in peripheral blood.

This study aimed to identify active compounds from whole cannabis extracts and their synergistic mixtures, and to assess respective cytotoxic activity against CTCL cells.

This mixture induced cell cycle arrest and cell apoptosis. Significant cytotoxic activity of the corresponding mixture of pure phytocannabinoids further verified genuine interaction between S4 and S5.

We suggest that specifying formulations of synergistic active cannabis compounds and unraveling their modes of action may lead to new cannabis-based therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/32284791

“Cannabis sativa has been used by humanity for thousands of years. Various phytocannabinoids exhibit antitumor effects in a wide array of cell lines and animal models. We have shown that a certain synergistic mixture of phytocannabinoids derived from C. sativa extracts have significant cytotoxic activity against My-La and HuT-78 cell lines and against SPBL.

To conclude, active cannabis extract fractions and their synergistic combinations were cytotoxic to CTCL cell lines in in-vitro and to SPBL in ex-vivo studies. The defined S4+S5 formulation of synergistic phytocannabinoids induced cell cycle arrest and cell apoptosis, and affected multiple biological pathways, including those associated with cancer. Based on this pre-clinical study new cannabis-based products that are based on precise composition of synergistically interacting compounds may be developed.”

https://www.oncotarget.com/article/27528/text/

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The effects of cannabinoids in exemestane-resistant breast cancer cells: PS181.

“Exemestane is one of the aromatase inhibitors (AI) used as first line treatment for estrogen-receptor positive breast cancer in post-menopausal women. Exemestane acts by inhibiting aromatase, the enzyme responsible for the conversion of androgens to estrogens and also by promoting apoptosis of breast cancer cells. Nevertheless, despite its therapeutic success, this AI, after prolonged treatment, can induce acquired resistance, which causes tumor relapse. Therefore, it is important to find new strategies to overcome resistance in order to improve breast cancer treatment.

Considering that the development of resistance is the main reason for endocrine treatment failure, our group decided to explore the ability of three cannabinoids, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and anandamide (AEA), to reverse resistance to exemestane. The THC and CBD are phytocannabinoids derived from the plant Cannabis sativa (marijuana) whereas AEA is an endocannabinoid. For that, it was used LTEDaro cells, a long-term estrogen deprived ER+ breast cancer cell line that mimics resistance to exemestane. These cells were treated with exemestane in combination with two phytocannabinoids, CBD and THC, and the endocannabinoid AEA.

The presence of CB1 and CB2 in LTEDaro cells was confirmed by Western blot analysis and the effects of the combination of cannabinoids with exemestane were evaluated by MTT and LDH assays. Cell morphology was analyzed by Giemsa and Hoechst staining.

Results: Our results demonstrate that all the cannabinoids induce a decrease in viability of exemestane-resistant cells, in a dose- and time-dependent manner, without LDH release. These results indicate that the studied cannabinoids, mainly THC and AEA, revert the resistance to exemestane, probably by inducing apoptosis, as observed in Giemsa/Hoechst stain by the presence of typical morphological features of apoptosis.

Conclusion: This study highlights the efficacy of using cannabinoids as a potential adjuvant treatment to revert resistance to AIs.”

https://www.ncbi.nlm.nih.gov/pubmed/32258721

https://journals.lww.com/pbj/fulltext/2017/09000/The_effects_of_cannabinoids_in.118.aspx

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Cannabinoids as anticancer therapeutic agents.

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 sativaCannabinoids 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

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

ijms-logo “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

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Editorial: The Canonical and Non-Canonical Endocannabinoid System as a Target in Cancer and Acute and Chronic Pain

frontiers in pharmacology – Retraction Watch“The endocannabinoid system (ECS) comprises the canonical receptor subtypes CB1R and CB2R and endocannabinoids (anandamide, AEA and 2-arachidonoylglycerol, 2-AG), and a “non-canonical” extended signaling network consisting of: (i) other fatty acid derivatives; (ii) the defined “ionotropic cannabinoid receptors” (TRP channels); other GPCRs (GPR55, PPARα); (iii) enzymes involved in the biosynthesis and degradation of endocannabinoids (FAAH and MAGL); and (iv) protein transporters (FABP family).The ECS is currently a hot topic due to its involvement in cancer and pain.

The current Research Topic highlights various ways the endocannabinoid system (ECS) can impact cancer and pain. Ramer et al. review the anticancer potential of the canonical and noncanonical endocannabinoid system. Morales and Jagerovic provide a much needed summary of cannabinoid ligands as promising antitumor agents in a wide variety of tumors, in contrast to their palliative applications. In their article, the authors classify cannabinoids with anticancer potential in endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Moreno et al. in their review explored the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers, showing the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it.

As an ensemble, these studies provide further fuel to the discussion and underline the potential for targeting the ECS at multiple levels to treat certain cancers and for pain relief. Importantly, they also help to move the focal point of the discussion beyond THC, CBD, and the cannonical receptors. Several of these reports either review or provide data to support the use of/targeting of other members of the ECS system as well as alternative natural products beyond THC and CBD.”

https://www.frontiersin.org/articles/10.3389/fphar.2020.00312/full

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The effects of cannabinoids on glioblastoma growth: A systematic review with meta-analysis of animal model studies.

European Journal of Pharmacology“Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant brain tumour, with a poor prognosis despite available surgical and radio-chemotherapy, rising the necessity for searching alternative therapies. Several preclinical studies evaluating the efficacy of cannabinoids in animal models of GBM have been described, but the diversity of experimental conditions and of outcomes hindered definitive conclusions about cannabinoids efficacy.

A search in different databases (Pubmed, Web of Science, Scopus and SciELO) was conducted during June 2019 to systematically identify publications evaluating the effects of cannabinoids in murine xenografts models of GBM. The tumour volume and number of animals were extracted, being a random effects meta-analysis of these results performed to estimate the efficacy of cannabinoids. The impact of different experimental factors and publication bias on the efficacy of cannabinoids was also assessed. Nine publications, which satisfied the inclusion criteria, were identified and subdivided in 22 studies involving 301 animals.

Overall, cannabinoid therapy reduced the fold of increase in tumour volume in animal models of GBM, when compared with untreated controls. The overall weighted standardized difference in means (WSDM) for the effect of cannabinoids was -1.399 (95% CI: -1.900 to -0.898; P-value<0.0001). Furthermore, treatment efficacy was observed for different types of cannabinoids, alone or in combination, and for different treatment durations.

Cannabinoid therapy was still effective after correcting for publication bias. The results indicate that cannabinoids reduce the tumour growth in animal models of GBM, even after accounting for publication bias.”

https://www.ncbi.nlm.nih.gov/pubmed/32145324

https://www.sciencedirect.com/science/article/abs/pii/S0014299920301473?via%3Dihub

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