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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Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia.

 Image result for cell death & disease“Anticancer properties of non-psychoactive cannabinoid cannabidiol (CBD) have been demonstrated on tumors of different histogenesis. Different molecular targets for CBD were proposed, including cannabinoid receptors and some plasma membrane ion channels. Here we have shown that cell lines derived from acute lymphoblastic leukemia of T lineage (T-ALL), but not resting healthy T cells, are highly sensitive to CBD treatment. CBD effect does not depend on cannabinoid receptors or plasma membrane Ca2+-permeable channels. Instead, CBD directly targets mitochondria and alters their capacity to handle Ca2+. At lethal concentrations, CBD causes mitochondrial Ca2+ overload, stable mitochondrial transition pore formation and cell death. Our results suggest that CBD is an attractive candidate to be included into chemotherapeutic protocols for T-ALL treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31611561

“Considering the pivotal role of mitochondria in oncogenic re-programming, CBD may be plausible candidate to be included into chemotherapeutic protocols.”

https://www.nature.com/articles/s41419-019-2024-0

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Cannabis use in cancer: a survey of the current state at BC Cancer before recreational legalization in Canada.

Image result for Curr Oncol.“Cancer patients experience multiple symptoms throughout their illness, and some report benefit from the use of cannabis. There are concerns that many patients are accessing products inappropriate for their situation and potentially putting themselves at risk.

In the present study, we aimed to capture the prevalence of cannabis use among cancer patients at BC Cancer before recreational legalization in Canada and to identify the reasons that patients take cannabis, the various routes of administration they use, and the reasons that prior users stopped.

RESULTS:

Of surveys sent to 2998 patients, 821 (27.4%) were returned and included in analysis. Of those respondents, 23% were currently using cannabis-based products, almost exclusively for medical purposes, and an additional 28% had been users in the past (most often recreationally). Of the patients currently using cannabis, 31% had medical authorization. The most common symptoms that the current users were targeting were pain, insomnia, nausea, and anxiety; many were also hoping for anticancer effects.

CONCLUSIONS:

More than half the respondents had tried cannabis at some time, and almost one quarter of respondents were currently taking cannabis to help manage their symptoms or treat their cancer, or both. Many more patients would consider use with appropriate guidance from a health care professional. More research is needed to inform physicians and patients about safe uses and doses and about the potential adverse effects of cannabis use.”

https://www.ncbi.nlm.nih.gov/pubmed/31548810

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Evaluation of the effects of cannabinoids CBD and CBG on human ovarian cancer cells in vitro

University of Huddersfield“Ovarian cancer, with over a 90% reoccurrence within 18 months of treatment, and approximately a 30% mortality rate after 5 years, is the leading cause of death in cases of gynaecological malignancies. Acquired resistance, and toxic side effects by clinically used agents are major challenges associated with current treatments, indicating the need for new approaches in ovarian cancer treatment.

Increased tumour cell proliferation associated with upregulation of cannabinoid (CB) receptors has been observed in ovarian cancer. As cannabinoids reported to bind to CB receptors, and can potentially modulate their downstream signalling, this raises the possibility of cannabinoids as potential anticancer drugs for ovarian cancer treatment.

Amongst the cannabinoids, non-psychoactive CBD and CBG have been shown to have anticancer activities towards prostate and colon cancer cells through multiple mechanisms of action. However, CBD and CBG have yet to be investigated in relation to ovarian cancer therapy either in vitro or in vivo.

Aim:

The aims of this study were to evaluate the potential cytotoxic effects of CBD and CBG in human ovarian cancer cells, their ability to potentiate existing clinically used agents for ovarian cancer, and to perform initial mode of action studies in vitro.

Conclusions:

Both CBD and CBG showed preferential cytotoxicity against the ovarian cancer cells analysed compared to the non-cancer cells; however, this was less than for carboplatin. Importantly, in contrast to carboplatin, CBD and CBG showed similar activity towards cisplatin sensitive and cisplatin resistant cells indicating distinctive mechanisms of action to platinum drugs.

Preferential cytotoxicity towards cancer cells in vitro and ability to potentiate carboplatin and overcome cisplatin resistance identify CBD and CBG as promising candidates that warrant further investigation, both in terms of detailed mechanism of action studies and also in vivo studies to assess whether this promising activity translates into an in vivo setting and their potential for further progression towards the clinic.”

http://eprints.hud.ac.uk/id/eprint/34866/

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Preclinical evidence on the anticancer properties of phytocannabinoids

Image result for CROSBI“Phytocannabinoids are unique terpenophenolic compounds predominantly produced in the glandular trichomes of the cannabis plant (Cannabis sativa L.). The delta-9- tetrahydrocannabinol (THC) is the main active constituent responsible for the plant’s psychoactive effect and, together with the non- psychoactive cannabidiol (CBD), the most investigated naturally occurring cannabinoid.

The first report on the antitumor properties of cannabis compounds appeared more than forty years ago, but the potential of targeting the endocannabinoid system in cancer has recently attracted increasing interest. Our study aimed to review the last decade’s findings on the anticancer potential of plant- derived cannabinoids and the possible mechanisms of their activity.

A large body of in vitro data has been accumulated demonstrating that phytocannabinoids affect a wide spectrum of tumor cells, including gliomas, neuroblastomas, hepatocarcinoma as well as skin, prostate, breast, cervical, colon, pancreatic, lung and hematological cancer.

It has been found that they can stop the uncontrolled growth of cancer cells through the cell-cycle arrest, inhibition of cell proliferation and induction of autophagy and apoptosis. They can also block all the steps of tumor progression, including tumor cell migration, adhesion and invasion as well as angiogenesis. The observed effects are mainly mediated by the cannabinoid CB1 and/or CB2 receptors, although some other receptors and mechanisms unrelated to receptor stimulation may also be involved.

The majority of available animal studies confirmed that phytocannabinoids are capable of effectively decreasing cancer growth and metastasis in vivo. THC was found to be effective against experimental glioma, liver, pancreatic, breast and lung cancer while CBD showed activity against glioma and neuroblastoma, melanoma, colon, breast, prostate and lung cancer. Further in vitro and in vivo studies also greatly support their use in combination with traditional chemotherapy or radiotherapy, which results in improved efficiency, attenuated toxicity or reduced drug resistance.

Taken together most of available preclinical results emphasize the extensive therapeutic potential of THC and CBD in various types of cancers. The potential clinical interest of cannabinoids is additionally suggested by their selectivity for tumor cells as well as their good tolerance and the absence of normal tissue toxicity, which are still the major limitations of most conventional drugs. The accumulated preclinical evidence strongly suggests the need for clinical testing of cannabinoids in cancer patients.”

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Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity.

molecules-logo“Mixtures of different Cannabis sativa phytocannabinoids are more active biologically than single phytocannabinoids. However, cannabis terpenoids as potential instigators of phytocannabinoid activity have not yet been explored in detail.

Terpenoid groups were statistically co-related to certain cannabis strains rich in Δ9-tetrahydrocannabinolic acid (THCA) or cannabidiolic acid (CBDA), and their ability to enhance the activity of decarboxylase phytocannabinoids (i.e., THC or CBD) was determined.

Analytical HPLC and GC/MS were used to identify and quantify the secondary metabolites in 17 strains of C. sativa, and correlations between cannabinoids and terpenoids in each strain were determined. Column separation was used to separate and collect the compounds, and cell viability assay was used to assess biological activity.

We found that in “high THC” or “high CBD” strains, phytocannabinoids are produced alongside certain sets of terpenoids. Only co-related terpenoids enhanced the cytotoxic activity of phytocannabinoids on MDA-MB-231 and HCT-116 cell lines.

This was found to be most effective in natural ratios found in extracts of cannabis inflorescence. The correlation in a particular strain between THCA or CBDA and a certain set of terpenoids, and the partial specificity in interaction may have influenced the cultivation of cannabis and may have implications for therapeutic treatments.”

https://www.ncbi.nlm.nih.gov/pubmed/31438532

https://www.mdpi.com/1420-3049/24/17/3031

“Anticancer Terpenoids” https://link.springer.com/chapter/10.1007/978-3-319-14027-8_5

“Anticancer effects of phytocannabinoids” https://www.ncbi.nlm.nih.gov/pubmed/28560402

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Opportunities for cannabis in supportive care in cancer.

 Related image“Cannabis has the potential to modulate some of the most common and debilitating symptoms of cancer and its treatments, including nausea and vomiting, loss of appetite, and pain.

However, the dearth of scientific evidence for the effectiveness of cannabis in treating these symptoms in patients with cancer poses a challenge to clinicians in discussing this option with their patients. A review was performed using keywords related to cannabis and important symptoms of cancer and its treatments.

Literature was qualitatively reviewed from preclinical models to clinical trials in the fields of cancer, human immunodeficiency virus (HIV), multiple sclerosis, inflammatory bowel disease, post-traumatic stress disorder (PTSD), and others, to prudently inform the use of cannabis in supportive and palliative care in cancer.

There is a reasonable amount of evidence to consider cannabis for nausea and vomiting, loss of appetite, and pain as a supplement to first-line treatments. There is promising evidence to treat chemotherapy-induced peripheral neuropathy, gastrointestinal distress, and sleep disorders, but the literature is thus far too limited to recommend cannabis for these symptoms.

Scant, yet more controversial, evidence exists in regard to cannabis for cancer- and treatment-related cognitive impairment, anxiety, depression, and fatigue. Adverse effects of cannabis are documented but tend to be mild.

Cannabis has multifaceted potential bioactive benefits that appear to outweigh its risks in many situations. Further research is required to elucidate its mechanisms of action and efficacy and to optimize cannabis preparations and doses for specific populations affected by cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/31413731

https://journals.sagepub.com/doi/10.1177/1758835919866362

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New approaches to cancer therapy: combining Fatty Acid Amide Hydrolase (FAAH) inhibition with Peroxisome Proliferator-Activated Receptors (PPARs) activation.

 Go to Volume 0, Issue ja“Over the course of the last decade, Peroxisome Proliferator-Activated Receptors (PPARs) have been identified as part of the cannabinoid signaling system: both phytocannabinoids and endocannabinoids are capable of binding and activating these nuclear receptors. Fatty Acid Amide Hydrolase (FAAH) hydrolyzes the endocannabinoid Anandamide and other N-Acylethanolamines. These substances have been shown to have numerous anti-cancer effects, and indeed the inhibition of FAAH has multiple beneficial effects that are mediated by PPARα subtype and by PPARγ subtype, especially antiproliferation and activation of apoptosis. The substrates of FAAH are also PPAR agonists, which explains the PPAR-mediated effects of FAAH inhibitors. Much like cannabinoid ligands and FAAH inhibitors, PPARγ agonists show antiproliferative effects on cancer cells, suggesting that additive or synergistic effects may be achieved through the positive modulation of both signaling systems. In this perspective, we discuss the development of novel FAAH inhibitors able to directly act as PPAR agonists and their promising utilization as leads for the discovery of highly effective anti-cancer compounds.”

https://www.ncbi.nlm.nih.gov/pubmed/31407888

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00885

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Flavonoid Derivative of Cannabis Demonstrates Therapeutic Potential in Preclinical Models of Metastatic Pancreatic Cancer.

Image result for frontiers oncology“Pancreatic cancer is particularly refractory to modern therapies, with a 5-year survival rate for patients at a dismal 8%.

One of the significant barriers to effective treatment is the immunosuppressive pancreatic tumor microenvironment and development of resistance to treatment. New treatment options to increase both the survival and quality of life of patients are urgently needed.

This study reports on a new non-cannabinoid, non-psychoactive derivative of cannabis, termed FBL-03G, with the potential to treat pancreatic cancer.

In vitro results show major increase in apoptosis and consequential decrease in survival for two pancreatic cancer models- Panc-02 and KPC pancreatic cancer cells treated with varying concentrations of FBL-03G and radiotherapy.

Meanwhile, in vivo results demonstrate therapeutic efficacy in delaying both local and metastatic tumor progression in animal models with pancreatic cancer when using FBL-03G sustainably delivered from smart radiotherapy biomaterials.

Repeated experiments also showed significant (P < 0.0001) increase in survival for animals with pancreatic cancer compared to control cohorts.

The findings demonstrate the potential for this new cannabis derivative in the treatment of both localized and advanced pancreatic cancer, providing impetus for further studies toward clinical translation.”

https://www.ncbi.nlm.nih.gov/pubmed/31396485

“In this study, a flavonoid derivative of cannabis demonstrates significant therapy potential in the treatment of pancreatic cancer, including radio-sensitizing and cancer metastasis treatment potential. The results justify further studies to optimize therapy outcomes toward clinical translation.”

https://www.frontiersin.org/articles/10.3389/fonc.2019.00660/full

“Flavonoids as anticancer agents: structure-activity relationship study.”  https://www.ncbi.nlm.nih.gov/pubmed/12678721

“The antitumor activities of flavonoids.”  https://www.ncbi.nlm.nih.gov/pubmed/16097445

“Anticancer properties of flavonoids: roles in various stages of carcinogenesis.”  https://www.ncbi.nlm.nih.gov/pubmed/21644918

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Cannabinoid Signaling in Cancer.

“The family of chemical structures that interact with a cannabinoid receptor are broadly termed cannabinoids. Traditionally known for their psychotropic effects and their use as palliative medicine in cancer, cannabinoids are very versatile and are known to interact with several orphan receptors besides cannabinoid receptors (CBR) in the body. Recent studies have shown that several key pathways involved in cell growth, differentiation and, even metabolism and apoptosis crosstalk with cannabinoid signaling. Several of these pathways including AKT, EGFR, and mTOR are known to contribute to tumor development and metastasis, and cannabinoids may reverse their effects, thereby by inducing apoptosis, autophagy and modulating the immune system. In this book chapter, we explore how cannabinoids regulate diverse signaling mechanisms in cancer and immune cells within the tumor microenvironment and whether they impart a therapeutic effect. We also provide some important insight into the role of cannabinoids in cellular and whole body metabolism in the context of tumor inhibition. Finally, we highlight recent and ongoing clinical trials that include cannabinoids as a therapeutic strategy and several combinational approaches towards novel therapeutic opportunities in several invasive cancer conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/31332734

https://link.springer.com/chapter/10.1007%2F978-3-030-21737-2_4

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