Antitumor Activity of Abnormal Cannabidiol and Its Analog O-1602 in Taxol-Resistant Preclinical Models of Breast Cancer.

Image result for frontiers in pharmacology“Cannabinoids exhibit anti-inflammatory and antitumorigenic properties.

Contrary to most cannabinoids present in the Cannabis plant, some, such as O-1602 and abnormal cannabidiol, have no or only little affinity to the CB1 or CB2 cannabinoid receptors and instead exert their effects through other receptors.

Here, we investigated whether the synthetic regioisomers of cannabidiol, abnormal cannabidiol, and a closely related compound, O-1602, display antitumorigenic effects in cellular models of breast cancer and whether it could reduce tumorigenesis in vivo.

Several studies have shown the effects of cannabinoids on chemotherapy-sensitive breast cancer cell lines, but less is known about the antitumorigenic effects of cannabinoids in chemotherapy-resistant cell lines.

Paclitaxel-resistant MDA-MB-231 and MCF-7 breast cancer cell lines were used to study the effect of O-1602 and abnormal cannabidiol on viability, apoptosis, and migration. The effects of O-1602 and abnormal cannabidiol on cell viability were completely blocked by the combination of GPR55 and GPR18-specific siRNAs. Both O-1602 and abnormal cannabidiol decreased viability in paclitaxel-resistant breast cancer cells in a concentration-dependent manner through induction of apoptosis. The effect of these cannabinoids on tumor growth in vivo was studied in a zebrafish xenograft model. In this model, treatment with O-1602 and abnormal cannabidiol (2 µM) significantly reduced tumor growth.

Our results suggest that atypical cannabinoids, like O-1602 and abnormal cannabidiol, exert antitumorigenic effects on paclitaxel-resistant breast cancer cells. Due to their lack of central sedation and psychoactive effects, these atypical cannabinoids could represent new leads for the development of additional anticancer treatments when resistance to conventional chemotherapy occurs during the treatment of breast and possibly other cancers.”

https://www.ncbi.nlm.nih.gov/pubmed/31611800

“Our results suggest that some cannabinoids acting through the GPR55 and/or GPR18 receptors can be helpful in inducing apoptosis in breast cancer cell lines that are unresponsive to paclitaxel. The effects of O-1602 and Abn-CBD on cell viability were observed both in vitro and in a zebrafish xenograft model. These drugs were also reducing cell migration. Taken together, even if no synergistic antitumor effect is always observed when cannabinoids and chemotherapeutic agents are combined as an anticancer treatment, cannabinoids can still provide anticancer benefits on top of their palliative effects. This is particularly important in the context of cancers that have developed resistance to current chemotherapies.”

https://www.frontiersin.org/articles/10.3389/fphar.2019.01124/full

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Emerging Class of Omega-3 Fatty Acid Endocannabinoids & Their Derivatives.

Prostaglandins & Other Lipid Mediators

“Cannabinoid receptor activation is involved in homeostatic regulation of the body. These receptors are activated by cannabinoids, that include the active constituents of Cannabis sativa as well as endocannabinoids (eCBs). The eCBs are endogenously synthesized from the omega-6 and omega-3 polyunsaturated fatty acids (PUFAs). In summary, we outline the novel findings regarding a growing class of signaling molecules, omega-3 eCBs, that can control the physiological and pathophysiological processes in the body.” https://www.ncbi.nlm.nih.gov/pubmed/31085370

“Anti-inflammatory ω-3 endocannabinoid epoxides.”  https://www.ncbi.nlm.nih.gov/pubmed/28687674

“Antitumorigenic Properties of Omega-3 Endocannabinoid Epoxides.” https://www.ncbi.nlm.nih.gov/pubmed/29856219

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Enhancing the Therapeutic Efficacy of Cancer Treatment With Cannabinoids

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“Many in vitro and in vivo studies have reported on the antitumorigenic effects of plant-derived cannabinoids (CBDs) and their synthetic analogs, including effects in inducing apoptosis and inhibiting tumor cell growth and metastasis.

Over the years, many in vitro and in vivo studies have shown the antineoplastic effects of cannabinoids (CBDs), with reports advocating for investigations of combination therapy approaches that could better leverage these effects in clinical translation.

This study explores the potential of combination approaches employing CBDs with radiotherapy (RT) or smart biomaterials toward enhancing therapeutic efficacy during treatment of pancreatic and lung cancers. In in vitro studies, clonogenic assay results showed greater effective tumor cell killing, when combining CBDs and RT. Meanwhile, in vivo study results revealed major increase in survival when employing smart biomaterials for sustained delivery of CBDs to tumor cells. The significance of these findings, considerations for further research, and viable roadmap to clinical translation are discussed.

The advantage of combining CBDs with other therapies is that this may allow simultaneous targeting of tumor progression at different levels, while minimizing toxicities for these therapies relative to toxicities from higher doses when used as monotherapies.”

“Cannabis Science Announces the Second Frontiers Peer-Reviewed Publication of its Research Results on the Use of Cannabinoids in the Treatment of Cancers”  https://globenewswire.com/news-release/2018/05/01/1493854/0/en/Cannabis-Science-Announces-the-Second-Frontiers-Peer-Reviewed-Publication-of-its-Research-Results-on-the-Use-of-Cannabinoids-in-the-Treatment-of-Cancers.html

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Antitumorigenic targets of cannabinoids – current status and implications.

“Molecular structures of the endocannabinoid system have gained interest as potential pharmacotherapeutical targets for systemic cancer treatment.

The present review covers the contribution of the endocannabinoid system to cancer progression. Particular focus will be set on the accumulating preclinical data concerning antimetastatic, anti-invasive and anti-angiogenic mechanisms induced by cannabinoids.

Expert opinion: The main goal of targeting endocannabinoid structures for systemic anticancer treatment is the comparatively good safety profile of cannabinoid compounds.

In addition, antitumorigenic mechanisms of cannabinoids are not restricted to a single molecular cascade but involve multiple effects on various levels of cancer progression such as angiogenesis and metastasis. Particularly the latter effect has gained interest for pharmacological interventions.

Thus, drugs aiming at the endocannabinoid system may represent potential “antimetastatics” for an upgrade of a future armamentarium against cancer diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27070944

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

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Evaluation of cannabinoid CB1 and CB2 receptors expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients’ survival.

Tumor Biology

“Cannabinoid receptors (CB1R and CB2R) constitute essential members of the endocannabinoid system (ECS) which participates in many different functions indispensable to homeostatic regulation in several tissues, exerting also antitumorigenic effects. The present study aimed to assess the clinical significance of CB1R and CB2R protein expression in mobile tongue squamous cell carcinoma (SCC). The present study provides evidence that CB1R and CB2R may play a role in the pathophysiological aspects of the mobile tongue SCC and even each molecule may constitute a potential target for the development of novel anti-cancer drugs for this type of malignancy.” http://www.ncbi.nlm.nih.gov/pubmed/26459312

https://link.springer.com/article/10.1007%2Fs13277-015-4182-8

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CANNABINOIDS INCREASE LUNG CANCER CELL LYSIS BY LYMPHOKINE-ACTIVATED KILLER CELLS VIA UPREGULATION OF ICAM-1.

“Cannabinoids have been shown to promote the expression of the intercellular adhesion molecule 1 (ICAM-1) on lung cancer cells as part of their anti-invasive and antimetastatic action…

Cannabidiol (CBD), a non-psychoactive cannabinoid, enhanced the susceptibility of cancer cells to adhere to and subsequently lysed by LAK cells, with both effects being reversed by a neutralizing ICAM-1 antibody…

ICAM-1-dependent pro-killing effects were further confirmed for the phytocannabinoid Δ9-tetrahydrocannabinol (THC) and R(+)-methanandamide, a stable endocannabinoid analogue…

Altogether, our data demonstrate cannabinoid-induced upregulation of ICAM-1 on lung cancer cells to be responsible for increased cancer cell susceptibility to LAK cell-mediated cytolysis.

These findings provide proof for a novel antitumorigenic mechanism of cannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/25069049

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

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COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

Figure 7.

“Within the last decade, evidence has been accumulated to suggest an antitumorigenic action of cannabinoids elicited via induction of apoptosis and alternative anticarcinogenic mechanisms… cannabidiol has been shown to elicit pronounced proapoptotic or autophagic effects on different types of tumor cells

This study investigates the role of COX-2 and PPAR-γ in cannabidiol’s proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis… our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ…

Collectively, our data strengthen the notion that activation of PPAR-γ may present a promising target for lung cancer therapy.

In addition and to the best of our knowledge, this is the first report to provide an inhibitor-proven tumor-regressive mechanism of cannabidiolin vivo as well as a proapoptotic mechanism confirmed by use of primary lung tumor cells.

Against this background and considering recent findings supporting a profound antimetastatic action of cannabidiol, this cannabinoid may represent a promising anticancer drug.”

http://mct.aacrjournals.org/content/12/1/69.long

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

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Cannabidiol Inhibits Growth and Induces Programmed Cell Death in Kaposi Sarcoma–Associated Herpesvirus-Infected Endothelium

“Kaposi sarcoma is the most common neoplasm caused by Kaposi sarcoma–associated herpesvirus (KSHV). Current treatments for Kaposi sarcoma can inhibit tumor growth but are not able to eliminate KSHV from the host. When the host’s immune system weakens, KSHV begins to replicate again, and active tumor growth ensues. New therapeutic approaches are needed.

Cannabidiol (CBD), a plant-derived cannabinoid, exhibits promising antitumor effects without inducing psychoactive side effects. CBD is emerging as a novel therapeutic for various disorders, including cancer.

In this study, we investigated the effects of CBD both on the infection of endothelial cells (ECs) by KSHV and on the growth and apoptosis of KSHV-infected ECs, an in vitro model for the transformation of normal endothelium to Kaposi sarcoma….

Cannabidiol (CBD) was first isolated in 1940. It is a major component of the plant Cannabis sativa, which is also the source of Δ9-tetrahydrocannabinol (Δ9-THC). Due to its multiple biological activities, CBD has been identified as a potential clinical agent. Moreover, CBD affects these activities without the psychoactive side effects that typify Δ9-THC. Recent studies have documented the potential antitumorigenic properties of CBD in the treatment of various neoplasms, including breast cancer, lung cancer, bladder cancer, glioblastoma,and leukemia.CBD induces these effects through a variety of mechanisms and signaling pathways

CBD has been evaluated clinically for the treatment of various conditions, including anxiety, psychosis, and pain. In contrast to other members of the cannabinoid family, CBD has a strong safety profile and induces no psychotropic effects.Therefore, it has become an attractive agent in the search for new anticancer therapies.Our current study demonstrated that CBD preferentially enhanced apoptosis and inhibited the proliferation of KSHV-infected endothelial cells. This selective targeting of KSHV-induced neoplasia suggests that CBD may have a desirable therapeutic index when used to treat cancer. Moreover, a recent study demonstrated that CBD can be delivered effectively by nasal and transdermal routes, which may be particularly valuable for the treatment of Kaposi sarcoma oral or skin lesions.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527984/

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