Cannabidiol Effectively Promoted Cell Death in Bladder Cancer and the Improved Intravesical Adhesion Drugs Delivery Strategy Could Be Better Used for Treatment

Posted on September 14, 2021 by David Worrell

“Cannabidiol (CBD), a primary bioactive phytocannabinoid extracted from hemp, is reported to possess potent anti-tumorigenic activity in multiple cancers.

However, the effects of CBD on bladder cancer (BC) and the underlying molecular mechanisms are rarely reported.

Here, several experiments proved that CBD promoted BC cells (T24, 5637, and UM-UC-3) death.

In summary, this work demonstrates that CBD may become a novel reliable anticancer drug and the developed intravesical adhesion system is expected to turn into a potential means of BC chemotherapy drug delivery.

We believe that our study makes a significant contribution to the field because these results can be developed as a promising strategy for a safer and more efficient anticancer therapy.”

https://www.mdpi.com/1999-4923/13/9/1415/htm

THC Reduces Ki67-Immunoreactive Cells Derived from Human Primary Glioblastoma in a GPR55-Dependent Manner

Posted on April 5, 2021 by David Worrell

“Glioblastoma (GBM) is the most frequent malignant tumor of the central nervous system in humans with a median survival time of less than 15 months.

∆⁹-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best-characterized components of Cannabis sativa plants with modulating effects on cannabinoid receptors 1 and 2 (CB₁ and CB₂) and on orphan receptors such as GPR18 or GPR55. Previous studies have demonstrated anti-tumorigenic effects of THC and CBD in several tumor entities including GBM, mostly mediated via CB₁ or CB₂.

In this study, we investigated the non-CB₁/CB₂ effects of THC on the cell cycle of GBM cells isolated from human tumor samples.

Cell cycle entry was measured after 24 h upon exposure by immunocytochemical analysis of Ki67 as proliferation marker. The Ki67-reducing effect of THC was abolished in the presence of CBD, whereas CBD alone did not cause any changes. To identify the responsible receptor for THC effects, we first characterized the cells regarding their expression of different cannabinoid receptors: CB₁, CB₂, GPR18, and GPR55. Secondly, the receptors were pharmacologically blocked by application of their selective antagonists AM281, AM630, O-1918, and CID16020046 (CID), respectively. All examined cells expressed the receptors, but only in presence of the GPR55 antagonist CID was the THC effect diminished. Stimulation with the GPR55 agonist lysophosphatidylinositol (LPI) revealed similar effects as obtained for THC. The LPI effects were also inhibited by CBD and CID, confirming a participation of GPR55 and suggesting its involvement in modifying the cell cycle of patient-derived GBM cells.”

https://pubmed.ncbi.nlm.nih.gov/33802282/

“Glioblastoma (GBM) is the most frequent primary brain tumor entity with poor prognosis and resistance to current standard therapies. Cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD) are discussed as promising compounds for individualized treatment, as they exert anti-tumor effects by binding to cannabinoid-specific receptors. However, their pharmacology is highly diverse and complex. The present study was designed to verify (1) whether cannabinoids show even any effect in GBM cells derived from primary human tumor samples and (2) to identify the receptor responsible for those effects. Our findings revealed that THC reduces the number of Ki67 immunoreactive nuclei, a cell cycle marker through the orphan cannabinoid receptor GPR55. The data suggest a therapeutic potential of cannabinoids in those GBM with functional and responsive GPR55.”

https://www.mdpi.com/2072-6694/13/5/1064

Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma

Posted on November 30, 2020 by David Worrell

Scientific Reports “Cannabidiol (CBD) has anti-tumorigenic activity. However, the anti-cancer effect of CBD on head and neck squamous cell carcinoma (HNSCC) remains unclear. The cytotoxicity of CBD on HNSCC was analyzed using cell survival and colony-forming assays in vitro.

CBD treatment significantly reduced migration/invasion and viability of HNSCC cells in a dose- and time-dependent manner. HNSCC mouse xenograft models revealed anti-tumor effects of CBD. Furthermore, combinational treatment with CBD enhanced the efficacy of chemotherapy drugs.

We identified CBD as a new potential anti-cancer compound for single or combination therapy of HNSCC.”

https://pubmed.ncbi.nlm.nih.gov/33244087/

In conclusion, our study determined the anti-tumorigenic potential of CBD. In addition, single treatment of CBD or co-treatment with chemotherapeutic agents promoted HNSCC cell death along with apoptosis and autophagy processes. Therefore, our study suggests that CBD can be an excellent therapeutic agent against HNSCC. Cannabidiol (CBD) is one of the components in the Cannabis sativa L. (marijuana) family of plants.”

https://www.nature.com/articles/s41598-020-77674-y

Anti-Tumorigenic Properties of Omega-3 Endocannabinoid Epoxides.

Posted on June 2, 2018 by David Worrell

“Accumulating studies have linked inflammation to tumor progression. Dietary omega-3 fatty acids including docosahexaenoic acid (DHA) have been shown to suppress tumor growth through their conversion to epoxide metabolites. Alternatively, DHA is converted enzymatically into docosahexaenoylethanolamide (DHEA), an endocannabinoid with anti-proliferative activity. Recently, we reported a novel class of anti-inflammatory DHEA-epoxides (EDP-EAs) that contain both ethanolamide and epoxide moieties. Herein we evaluate the anti-tumorigenic properties of EDP-EAs in an osteosarcoma model. First, we show ~80% increase in EDP-EAs in metastatic lungs versus normal mouse lungs. We found significant differences in the apoptotic and anti-migratory potency of the different EDP-EA regioisomers, which are partly mediated through cannabinoid receptor 1 (CB1). Furthermore, we synthesized derivatives of the most pro-apoptotic regioisomer. These derivatives had reduced hydrolytic susceptibility to fatty acid-amide hydrolase and increased CB1 binding. Collectively, we report a novel class of EDP-EAs that exhibit anti-angiogenic, anti-tumorigenic and anti-migratory properties in osteosarcoma.” https://www.ncbi.nlm.nih.gov/pubmed/29856219 https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00243

“Omega-3 Fatty Byproducts May Have Anticancer Effects.” https://scienceblog.com/502227/omega-3-fatty-byproducts-may-have-anticancer-effects/

“Omega 3 fatty acids hold the key to stop cancer” http://www.thehansindia.com/posts/index/Health/2018-07-14/Omega-3-fatty-acids-hold-the-key-stop-cancer/398130

“Products of omega-3 fatty acid metabolism may have anticancer effects, study shows” https://medicalxpress.com/news/2018-07-products-omega-fatty-acid-metabolism.html

“Omega-3-derived cannabinoid may stop cancer. New research suggests that the body’s natural pain-killer, the “endocannabinoid system,” may also have cancer-fighting properties when “activated” by omega-3 fatty acids.” https://www.medicalnewstoday.com/articles/322482.php

“Omega-3 diet can do more than protecting your heart, it may keep cancer away” https://economictimes.indiatimes.com/magazines/panache/omega-3-diet-can-do-more-than-protecting-your-heart-it-may-keep-cancer-away/articleshow/64988681.cms

“Products of omega-3 fatty acid metabolism may have anticancer effects” https://www.sciencedaily.com/releases/2018/07/180713220137.htm

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The Role of Cannabinoids in the Treatment of Cancer in Pediatric Patients.

Posted on May 1, 2017 by David Worrell

“Cannabis has been used in folk medicine to alleviate pain, depression, amenorrhea, inflammation and numerous other medical conditions. In cancer patients specifically, cannabinoids are well known to exert palliative effects; their best-established use is the inhibition of chemotherapy-induced nausea and vomiting, but they are applied also to alleviate pain, stimulate appetite, and attenuate wasting. More recently, cannabinoids have gained special attention for their role in cancer cell proliferation and death. Anti-cancer efficacy of cannabinoids: The ability of cannabinoids to reduce tumor growth was reported for the first time by Munson et al. in 1975. They showed by in vitro and in vivo experiments that several phytocannabinoids, including THC, decreased Lewis lung adenocarcinoma proliferation in a dose-dependent manner. Nevertheless, it was not until the 2000s that the interest in these compounds as anti-cancer agents was renewed, predominantly due to the work of Guzman in gliomas, and the demonstration of cannabinoids’ anti-cancer effects on various types of tumors. The anti-tumorigenic effect of the endo- and phytocannabinoids was demonstrated in several in vitro and in vivo models of a wide variety of adult tumors including glioma, prostate, breast, leukemia, lymphoma, pancreas, melanoma, thyroid, colorectal and hepatocellular carcinoma tumors. Given our positive results, we suggest that non-THC cannabinoids such as CBD might provide a basis for the development of novel therapeutic strategies without the typical psychotropic effects of THC that limit its use in pediatric patients. Overall, the cannabinoids, and specifically the non-psychoactive CBD, may show future promise in the treatment of cancer” https://www.ima.org.il/FilesUpload/IMAJ/0/228/114216.pdf https://www.ima.org.il/imaj/ViewArticle.aspx?aId=4044 https://www.ncbi.nlm.nih.gov/pubmed/28457057]]>

Analysis of Omega-3 Fatty Acid Derived N-Acylethanolamines in Biological Matrices.

Posted on June 2, 2016 by David Worrell

“The adequate quantification of endocannabinoids can be complex due to their low endogenous levels and structural diversity. Therefore, advanced analytical approaches, such as LC-MS, are used to measure endocannabinoids in plasma, tissues, and other matrices. Recent work has shown that endocannabinoids that are synthesized from n-3 fatty acids, such as docosahexaenoylethanolamide (DHEA) and eicosapentaenoylethanolamide (EPEA), have anti-inflammatory and anti-tumorigenic properties and stimulate synapse formation in neurites. Here, an LC-MS based method for the quantification of n-3 endocannabinoids DHEA and EPEA which is also suited to measure a wider spectrum of endocannabinoids is described. The chapter contains a step-by-step protocol for the analysis of n-3 endocannabinoids in plasma, including sample collection and solid phase extraction, LC-MS analysis, and data processing. Modifications to the protocol that allow quantifying n-3 endocannabinoids in tissues and cell culture media will also be discussed. Finally, conditions that alter endocannabinoid concentrations are briefly discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/27245889

Cannabinoid receptor-2 agonist inhibits macrophage induced EMT in non-small cell lung cancer by downregulation of EGFR pathway.

Posted on January 12, 2016 by David Worrell

“JWH-015, a cannabinoid receptor 2 (CB2) agonist has tumor regressive property in various cancer types.

These data confer the impact of this cannabinoid on anti-proliferative and anti-tumorigenic effects, thus enhancing our understanding of its therapeutic efficacy in NSCLC.

Our findings open new avenues for cannabinoid receptor CB2 agonist-JWH-015 as a novel and potential therapeutic target based on EGFR downregulation mechanisms in NSCLC.”

http://www.ncbi.nlm.nih.gov/pubmed/26741322

Δ-9 Tetrahydrocannabinol inhibits growth and metastasis of lung cancer.

Posted on June 29, 2015 by David Worrell

Image result for harvard university logo

“Lung cancer is the major cause of cancer-related mortality worldwide.

Many of these over-express epidermal growth factor receptor (EGFR), and are usually highly aggressive and resistant to chemotherapy.

Recent studies have shown that Δ-9 Tetrahydrocannabinol (THC), the major component of Cannabis sativa, possess anti-tumor properties against various types of cancers.

However, not much is known about its effect on lung cancer. In this study, we sought to characterize the effect of THC on EGF-induced growth and metastasis of human non small lung cancer cell (NSCLC) lines A549 and SW-1573.

We demonstrate that these cell lines and primary tumor samples derived from lung cancer patients express cannabinoids receptors CB₁ and CB₂, the known targets for THC action.

We further show that THC inhibits EGF-induced growth in these cell lines.

In addition THC attenuated EGF-stimulated chemotaxis and chemoinvasion.

Next we characterized the effect of THC on in vivo lung cancer growth and metastasis in a murine model. A549 cells were implanted in SCID mice (n=6 per group) through subcutaneous and intravenous injections to generate subcutaneous and lung metastatic cancer, respectively. THC (5mg/kg body wt.) was administered once daily through intraperitoneal injections for 21 days. The mice were analyzed for tumor growth and lung metastasis.

A significant reduction (~50%) in tumor weight and volume were observed in THC treated animals compared to the vehicle treated animals.

THC treated animals also showed a significant (~60%) reduction in macroscopic lesions on the lung surface in comparison to vehicle treated control.

Immunohistochemical analysis of the tumor samples from THC treated animals revealed anti-proliferative and anti-angiogenic effects of THC with significant reduction in staining for Ki67, a proliferative marker and CD31, an endothelial marker indicative of vascularization. Investigation into the signaling events associated with reduced EGF-induced functional effects revealed that THC also inhibits EGF-induced Akt phosphorylation. Akt is a central signaling molecule of EGFR-mediated signaling pathways and it regulates a diverse array of cellular functions, including proliferation, angiogenesis, invasion and apoptosis.

Cumulatively, these studies indicate that THC has anti-tumorigenic and anti-metastatic effects against lung cancer. Novel therapies against EGFR overexpressing, aggressive and chemotherapy resistant lung cancers may include targeting the cannabinoids receptors.”

http://cancerres.aacrjournals.org/content/67/9_Supplement/4749.short

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

Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: Novel anti-tumor mechanisms of Cannabidiol in breast cancer.

Posted on February 11, 2015 by David Worrell

“The anti-tumor role and mechanisms of Cannabidiol (CBD), a non-psychotropic cannabinoid compound, are not well studied especially in triple-negative breast cancer (TNBC).

In the present study, we analyzed CBD’s anti-tumorigenic activity against highly aggressive breast cancer cell lines including TNBC subtype.

We show here -for the first time-that CBD significantly inhibits epidermal growth factor (EGF)-induced proliferation and chemotaxis of breast cancer cells.

Further studies revealed that CBD inhibits EGF-induced activation of EGFR, ERK, AKT and NF-kB signaling pathways as well as MMP2 and MMP9 secretion.

In addition, we demonstrated that CBD inhibits tumor growth and metastasis in different mouse model systems.

Analysis of molecular mechanisms revealed that CBD significantly inhibits the recruitment of tumor-associated macrophages in primary tumor stroma and secondary lung metastases…

In summary, our study shows -for the first time-that CBD inhibits breast cancer growth and metastasis through novel mechanisms by inhibiting EGF/EGFR signaling and modulating the tumor microenvironment.

These results also indicate that CBD can be used as a novel therapeutic option to inhibit growth and metastasis of highly aggressive breast cancer subtypes including TNBC, which currently have limited therapeutic options and are associated with poor prognosis and low survival rates.”

http://www.ncbi.nlm.nih.gov/pubmed/25660577

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

WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPARγ down-regulation.

Posted on April 7, 2014 by David Worrell

“Cannabinoids have been reported to possess anti-tumorigenic activity in cancer models…

Here, we show that the synthetic cannabinoid WIN55,212-2 (WIN)-induced apoptosis in colon cancer cell lines is accompanied by endoplasmic reticulum stress induction.

In conclusion, at our knowledge, our results are the first to show that the reduction of PPARγ levels contributes to WIN-induced colon carcinoma cell death by blocking the pro-survival autophagic response of cells.”

http://www.ncbi.nlm.nih.gov/pubmed/24696378

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