Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells.

Cancer Letters

“Cannabidiol (CBD), one of the compounds present in the marijuana plant, has anti-tumor properties, but its mechanism is not well known.

This study aimed to evaluate the apoptotic action of CBD in colorectal cancer (CRC) cells, and focused on its effects on the novel pro-apoptotic Noxa-reactive oxygen species (ROS) signaling pathway.

CBD experiments were performed using the CRC cell lines HCT116 and DLD-1. CBD induced apoptosis by regulating many pro- and anti-apoptotic proteins, of which Noxa showed significantly higher expression. To understand the relationship between Noxa and CBD-induced apoptosis, Noxa levels were downregulated using siRNA, and the expression of apoptosis markers decreased.

After ROS production was blocked, the level of Noxa also decreased, suggesting that ROS is involved in the regulation of Noxa, which along with ROS is a well-known pro-apoptotic signaling agents. As a result, CBD induced apoptosis in a Noxa-and-ROS-dependent manner.

Taken together, the results obtained in this study re-demonstrated the effects of CBD treatment in vivo, thus confirming its role as a novel, reliable anticancer drug.”

https://www.ncbi.nlm.nih.gov/pubmed/30660647

“Our results using cells, mice, and patient-derived cells strongly suggest, for the first time, that that CBD can cause Noxa-induced cell death. These results suggest that that CBD has important implications for the potential treatment of human CRC.”

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Naturally occurring compounds as pancreatic cancer therapeutics.

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“Naturally occurring small molecule compounds have long been in the spotlight of pancreatic cancer research as potential therapeutics to prevent cancer progression and sensitize chemoresistant tumors. The hope is that terminal pancreatic cancer patients receiving aggressive chemotherapy can benefit from an increase in treatment efficacy without adding further toxicity by way of utilizing natural compounds. While preclinical studies on a number of natural compounds, such as resveratrol, curcumin, rapalogs and cannabinoids, show promising preclinical results, little has translated into clinical practice, though a number of other compounds hold clinical potential. Nevertheless, recent advances in compound formulation may increase the clinical utility of these compounds.”

https://www.ncbi.nlm.nih.gov/pubmed/30459936

“The combination of natural products and standard of care chemotherapy has the potential to increase quality of life and lifespan in pancreatic cancer patients, even though a number of hurdles need to be overcome for routine clinical use.”  http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26234&path[]=81769

“Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum Stress–Related Genes. In conclusion, results presented here show that cannabinoids exert a remarkable antitumoral effect on pancreatic cancer cells in vitro and in vivo due to their ability to selectively induce apoptosis of these cells via activation of the p8-ATF-4-TRB3 proapoptotic pathway.”  http://cancerres.aacrjournals.org/content/66/13/6748

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The endocannabinoid signaling system in cancer

Image result for trends in pharmacological sciences“Changes in lipid metabolism are intimately related to cancer. Several classes of bioactive lipids play roles in the regulation of signaling pathways involved in neoplastic transformation and tumor growth and progression.

The endocannabinoid system, comprising lipid-derived endocannabinoids, their G-protein-coupled receptors (GPCRs), and the enzymes for their metabolism, is emerging as a promising therapeutic target in cancer.

This report highlights the main signaling pathways for the antitumor effects of the endocannabinoid system in cancer and its basic role in cancer pathogenesis, and discusses the alternative view of cannabinoid receptors as tumor promoters.

We focus on new players in the antitumor action of the endocannabinoid system and on emerging crosstalk among cannabinoid receptors and other membrane or nuclear receptors involved in cancer. We also discuss the enzyme MAGL, a key player in endocannabinoid metabolism that was recently recognized as a marker of tumor lipogenic phenotype.”

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(13)00044-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0165614713000448%3Fshowall%3Dtrue

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Light-activatable cannabinoid prodrug for combined and target-specific photodynamic and cannabinoid therapy.

“Cannabinoids are emerging as promising antitumor drugs. However, complete tumor eradication solely by cannabinoid therapy remains challenging. In this study, we developed a far-red light activatable cannabinoid prodrug, which allows for tumor-specific and combinatory cannabinoid and photodynamic therapy. This prodrug consists of a phthalocyanine photosensitizer (PS), reactive oxygen species (ROS)-sensitive linker, and cannabinoid. It targets the type-2 cannabinoid receptor (CB2R) overexpressed in various types of cancers. Upon the 690-nm light irradiation, the PS produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases the cannabinoid drug. We found that this unique multifunctional prodrug design offered dramatically improved therapeutic efficacy, and therefore provided a new strategy for targeted, controlled, and effective antitumor cannabinoid therapy.”

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Report of Objective Clinical Responses of Cancer Patients to Pharmaceutical-grade Synthetic Cannabidiol.

“Cannabinoids are widely used in the management of pain, nausea and cachexia in cancer patients. However, there has been no objective clinical evidence of any anticancer activity yet.

The aim of this study was to assess the effects of pharmaceutical-grade synthetic cannabidiol on a range of cancer patients.

RESULTS:

Clinical responses were seen in 92% of the 119 cases with solid tumours including a reduction in circulating tumour cells in many cases and in other cases, a reduction in tumour size, as shown by repeat scans. No side-effects of any kind were observed when using pharmaceutical grade synthetic cannabidiol.

CONCLUSION:

Pharmaceutical-grade synthetic cannabidiol is a candidate for treating breast cancer and glioma patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30275207

http://ar.iiarjournals.org/content/38/10/5831

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Bortezomib And Endocannabinoid/Endovanilloid System: A Synergism In Osteosarcoma.

Pharmacological Research

“Osteosarcoma is the most common primary malignant tumor of bone in children and adolescents.

Bortezomib (BTZ) is an approved anticancer drug, classified as a selective reversible inhibitor of the ubiquitin-dependent proteasome system, that leads to cancer cell cycle arrest and apoptosis reducing the invasion ability of Osteosarcoma cells in vitro. It also regulates the RANK/RANKL/OPG system, involved in the pathogenesis of bone tumors and in cell migration.

A side effect of BTZ is to induce painful sensory peripheral neuropathy which lead to cessation of therapy or dose reduction.

Recently BTZ has been evaluated in combination with Cannabinoids targeting CB1 receptor, demonstrating a promising synergic effect.

The Endocannabinoid/Endovanilloid (EC/EV) system includes two G protein-coupled receptors (CB1 and CB2), the Transient Potential Vanilloid 1 (TRPV1) channel and their endogenous ligands and enzymes.

CB1 and CB2 are expressed mainly in Central Nervous System and Immune Peripheral cells respectively. TRPV1 is also expressed in primary sensory neurons and is involved in pain modulation.

EC/EV system induces apoptosis, reduces invasion and cell proliferation in Osteosarcoma cell lines and is involved in bone metabolism.

We analyzed the effects of BTZ, alone and in combination with selective agonists at CB2 (JWH-133) and TRPV1 (RTX) receptors, in the Osteosarcoma cell line (HOS) on Apoptosis, Cell Cycle progression, migration and bone balance. We observed that the stimulation of CB2 and TRPV1 receptors increase the efficacy of BTZ in inducing apoptosis and reducing invasion, cell cycle progression and by modulating bone balance.

These data suggest the possibility to use BTZ, in combination with EC/EV agonists, in Osteosarcoma therapy reducing its dose and its side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30267762

https://www.sciencedirect.com/science/article/abs/pii/S1043661818310387

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Cannabinoid WIN 55,212-2 induces cell cycle arrest and apoptosis, and inhibits proliferation, migration, invasion, and tumor growth in prostate cancer in a cannabinoid-receptor 2 dependent manner.

The Prostate banner

“Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including in prostate cancer.

In the present study, we explored the anti-cancer effects of the synthetic cannabinoid WIN 55,212-2 (WIN) in prostate cancer.

RESULTS:

WIN significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in Go/G1 phase in a dose-dependent manner. Mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, Cdk4, and pRb. Pre-treatment with a CB2 antagonist, AM630, followed by treatment with WIN resulted in a reversal of the anti-proliferation and cell cycle arrest previously seen with WIN alone. In vivo, administration of WIN resulted in a reduction in the tumor growth rate compared to control (P < 0.05).

CONCLUSIONS:

The following study provides evidence supporting the use of WIN as a novel therapeutic for prostate cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/30242861

https://onlinelibrary.wiley.com/doi/abs/10.1002/pros.23720

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

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

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Targeting Glioma Initiating Cells With A Combined Therapy Of Cannabinoids And Temozolomide.

Biochemical Pharmacology

“Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve the survival of the patients suffering this devastating disease.

Previous observations by our group and others have shown that Δ9-Tetrahydrocannabinol (THC, the main active ingredient of marijuana) and other cannabinoids including cannabidiol (CBD) exert antitumoral actions in several animal models of cancer, including gliomas.

We also found that the administration of THC (or of THC + CBD at a 1:1 ratio) in combination with temozolomide, the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts.

In this work we investigated the effect of the combination of TMZ and THC:CBD mixtures containing different ratios of the two cannabinoids in preclinical glioma models, including those derived from GICs.

Our findings show that TMZ + THC:CBD combinations containing a higher proportion of CDB (but not TMZ + CBD alone) produce a similar antitumoral effect as the administration of TMZ together with THC and CBD at a 1:1 ratio in xenografts generated with glioma cell lines. In addition, we also found that the administration of TMZ + THC:CBD at a 1:1 ratio reduced the growth of orthotopic xenografts generated with GICs derived from GBM patients and enhanced the survival of the animals bearing these intracranial xenografts.

Remarkably, the antitumoral effect observed in GICs-derived xenografts was stronger when TMZ was administered together with cannabinoid combinations containing a higher proportion of CBD. These findings support the notion that the administration of TMZ together with THC:CBD combinations – and specifically those containing a higher proportion of CBD – may be therapeutically explored to target the population of GICs in GBM.”

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Cannabinoids in cancer treatment: Therapeutic potential and legislation.

Bosnian Journal of Basic Medical Sciences

“The plant Cannabis sativa L. has been used as an herbal remedy for centuries and is the most important source of phytocannabinoids.

The endocannabinoid system (ECS) consists of receptors, endogenous ligands (endocannabinoids) and metabolizing enzymes, and plays an important role in different physiological and pathological processes.

Phytocannabinoids and synthetic cannabinoids can interact with the components of ECS or other cellular pathways and thus affect the development/progression of diseases, including cancer.

In cancer patients, cannabinoids have primarily been used as a part of palliative care to alleviate pain, relieve nausea and stimulate appetite.

In addition, numerous cell culture and animal studies showed antitumor effects of cannabinoids in various cancer types.

Here we reviewed the literature on anticancer effects of plant-derived and synthetic cannabinoids, to better understand their mechanisms of action and role in cancer treatment. We also reviewed the current legislative updates on the use of cannabinoids for medical and therapeutic purposes, primarily in the EU countries.

In vitro and in vivo cancer models show that cannabinoids can effectively modulate tumor growth, however, the antitumor effects appear to be largely dependent on cancer type and drug dose/concentration.

Understanding how cannabinoids are able to regulate essential cellular processes involved in tumorigenesis, such as progression through the cell cycle, cell proliferation and cell death, as well as the interactions between cannabinoids and the immune system, are crucial for improving existing and developing new therapeutic approaches for cancer patients.

The national legislation of the EU Member States defines the legal boundaries of permissible use of cannabinoids for medical and therapeutic purposes, however, these legislative guidelines may not be aligned with the current scientific knowledge.”

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