Enhancing the Therapeutic Efficacy of Cancer Treatment With Cannabinoids

May 2, 2018, 6:28 am

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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.”

https://www.frontiersin.org/articles/10.3389/fonc.2018.00114/full

“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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Is Cannabidiol a Promising Substance for New Drug Development? A Review of its Potential Therapeutic Applications.

May 19, 2018, 4:29 am

≫ Next: A peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain.

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“The pharmacological importance of cannabidiol (CBD) has been in study for several years.

CBD is the major nonpsychoactive constituent of plant Cannabis sativa and its administration is associated with reduced side effects.

Currently, CBD is undergoing a lot of research which suggests that it has no addictive effects, good safety profile and has exhibited powerful therapeutic potential in several vital areas.

It has wide spectrum of action because it acts through endocannabinoid receptors; CB1 and CB2 and it also acts on other receptors, such as GPR18, GPR55, GPR 119, 5HT1A, and TRPV2.

This indicates its therapeutic value for numerous medical conditions because of its neuroprotective and immunomodulatory properties.

Potential therapeutic applications of CBD include, analgesic, anti-inflammatory, anxiolytic, anti-arthritic, anti-depressant, anti-Alzheimer disease, anti-ischemic, neuroprotective, and anti-fibrotic.

More promising areas appear to include diabetes and cancer where CBD exhibits lesser side effects and more therapeutic benefits as compared to recent available medical therapies.

Hence, CBD is a promising substance for the development of new drug. However further research and clinical studies are required to explore its complete potential.”

 https://www.ncbi.nlm.nih.gov/pubmed/29773016

http://www.dl.begellhouse.com/journals/6dbf508d3b17c437,642ad759707fc517,35856ff546e47ff9.html

A peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain.

May 22, 2018, 3:41 am

≫ Next: Endocannabinoid system and anticancer properties of cannabinoids

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“Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain.

Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients’ quality of life.

In contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP.

Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP.

Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects.

Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP.”

 https://www.ncbi.nlm.nih.gov/pubmed/29781960

https://insights.ovid.com/crossref?an=00006396-900000000-98957

Endocannabinoid system and anticancer properties of cannabinoids

May 24, 2018, 4:21 am

≫ Next: Cannabinoids in Glioblastoma Therapy: New Applications for Old Drugs

≪ Previous: A peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain.

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“Cannabinoids impact human body by binding to cannabinoids receptors (CB1 and CB2).

The two main phytocannabinoids are Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD).

THC interacts with CB1 receptors occurring in central nervous system and is responsible for psychoactive properties of marijuana. CBD has low affinity to CB1 receptor, has no psychoactive characteristics and its medical applications can be wider.

CB receptors are part of a complex machinery involved in regulation of many physiological processes – endocannabinoid system.

Cannabinoids have found some applications in palliative medicine, but there are many reports concerning their anticancer affects.

Agonists of CB1 receptors stimulate accumulation of ceramides in cancer cells, stress of endoplasmic reticulum (ER stress) and, in turn, apoptosis. Effects of cannabinoids showing low affinity to CB receptors is mediated probably by induction of reactive oxygen species production.

Knowledge of antitumor activity of cannabinoids is still based only on preclinical studies and there is a necessity to conduct more experiments to assess the real potential of these compounds.”

https://content.sciendo.com/view/journals/fobio/12/1/article-p11.xml

Cannabinoids in Glioblastoma Therapy: New Applications for Old Drugs

May 24, 2018, 4:42 am

≫ Next: Cannabinoids as a Promising Therapeutic Approach for the Treatment of Glioblastoma Multiforme: A Literature Review

≪ Previous: Endocannabinoid system and anticancer properties of cannabinoids

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“Glioblastoma (GBM) is the most malignant brain tumor and one of the deadliest types of solid cancer overall. Despite aggressive therapeutic approaches consisting of maximum safe surgical resection and radio-chemotherapy, more than 95% of GBM patients die within 5 years after diagnosis. Thus, there is still an urgent need to develop novel therapeutic strategies against this disease.

Accumulating evidence indicates that cannabinoids have potent anti-tumor functions and might be used successfully in the treatment of GBM.

This review article summarizes the latest findings on the molecular effects of cannabinoids on GBM, both in vitro and in (pre-) clinical studies in animal models and patients.

The therapeutic effect of cannabinoids is based on reduction of tumor growth via inhibition of tumor proliferation and angiogenesis but also via induction of tumor cell death. Additionally, cannabinoids were shown to inhibit the invasiveness and the stem cell-like properties of GBM tumors. Recent phase II clinical trials indicated positive results regarding the survival of GBM patients upon cannabinoid treatment.

Apart from a direct killing effect on tumor cells, cannabinoids can also induce cell cycle arrest thereby inhibiting tumor cell proliferation.

In conclusion, cannabinoids show promising anti-neoplastic functions in GBM by targeting multiple cancer hallmarks such as resistance to programmed cell death, neoangiogenesis, tissue invasion or stem cell-induced replicative immortality.

The effects of cannabinoids can be potentially enhanced by combination of different cannabinoids with each other or with chemotherapeutic agents. This requires, however, a detailed understanding of cannabinoid-induced molecular mechanisms and pharmacological effects.

Ultimately, these findings might foster the development of improved therapeutic strategies against GBM and, perhaps, other diseases of the nervous system as well.”

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00159/full

Cannabinoids as a Promising Therapeutic Approach for the Treatment of Glioblastoma Multiforme: A Literature Review

May 24, 2018, 5:14 am

≫ Next: Cannabinoids as potential new therapy for the treatment of gliomas

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“Gliobalstoma multiforme (GBM) or grade 4 astrocytoma is the most malignant form of primary brain tumor. Treatment of glioblastoma is difficult despite of surgery, radiotherapy and chemotherapy. Patients with glioblastoma survive for less than 12 months.

Considering to biology function of glioblastoma, researchers have recently offered new therapeutic approaches such as cannabinoid therapy for glioblastoma.

Cannabinoids are active compounds of Cannabis sativa that operate in the body similar to endogenous canabinoids –the endocannabinoids- through cell surface receptors.

It is interesting that cannabinoids could exert a wide spectrum from antiproliferative effects in condition of the cell culture, animal models of glioblastoma and clinical trials.

As a result, Cannabinoids seem to modulate intracellular signaling pathways and the endoplasmic reticulum stress response in glioma cells.

Those play antitumoral effects through apoptosis induction and inhibition of glioblastoma angiogenesis.

The goal of this study was to discuss cannabinoid therapy and also what cellular mechanisms are involved in the tumoricidal effect of the cannabinoids.

In this review article, we will focus on cannabinoids, their receptor dependent functional roles against glioblastoma acccording to growth, angiogenesis, metastasis, and future purposes in exploring new possible therapeutic opportunities.”

http://journals.sbmu.ac.ir/Neuroscience/article/view/13655

Cannabinoids as potential new therapy for the treatment of gliomas

May 24, 2018, 5:25 am

≫ Next: Targeting cannabinoid receptors in gastrointestinal cancers for therapeutic uses: current status and future perspectives

≪ Previous: Cannabinoids as a Promising Therapeutic Approach for the Treatment of Glioblastoma Multiforme: A Literature Review

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“Gliomas constitute the most frequent and malignant primary brain tumors. Current standard therapeutic strategies (surgery, radiotherapy and chemotherapeutics, e.g., temozolomide, carmustin or carboplatin) for their treatment are only palliative and survival diagnosis is normally 6-12 months.

The development of new therapeutic strategies for the management of gliomas is therefore essential.

Interestingly, cannabinoids have been shown to exert antiproliferative effects on a wide spectrum of cells in culture.

Of interest, cannabinoids have displayed a great potency in reducing glioma tumor growth either in vitro or in animal experimental models, curbing the growth of xenografts generated by subcutaneous or intratecal injection of glioma cells in immune-deficient mice.

Moreover, cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of nontransformed counterparts.

A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects, and may set the basis for further studies aimed at better evaluating the potential anticancer activity of cannabinoids.”

https://www.researchgate.net/publication/5761000_Cannabinoids_as_potential_new_therapy_for_the_treatment_of_gliomas

Targeting cannabinoid receptors in gastrointestinal cancers for therapeutic uses: current status and future perspectives

May 24, 2018, 10:14 am

≫ Next: Novel therapeutic applications of cannabinoids in cancer disease

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“A number of studies have consistently shown that cannabinoids are able to prevent or reduce carcinogenesis in different animal models of colon cancer.

Cannabinoids, via CB₁ and possibly CB₂ receptors, suppress proliferation and migration and stimulate apoptosis in colorectal cancer cells.

Convincing scientific evidence suggests that cannabinoids, in addition to their well-known use in palliative care in oncology (e.g. improvement of appetite, attenuation of nausea associated to antitumoral medicines, alleviation of moderate neuropathic pain) can reduce, via antiproliferative and proapoptotic as well as by inhibiting angiogenesis, invasion and metastasis or by attenuating inflammation, the growth of cancer cells and hinder the development of experimental colon carcinogenesis in vivo.”

https://www.tandfonline.com/doi/full/10.1080/17474124.2017.1367663?src=recsys

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Novel therapeutic applications of cannabinoids in cancer disease

May 24, 2018, 10:40 am

≫ Next: Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.

≪ Previous: Targeting cannabinoid receptors in gastrointestinal cancers for therapeutic uses: current status and future perspectives

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“The present review shows that cannabinoids exert their anti-cancer effects in a number of ways and in a variety of tissues.

The endocannabinoid system is an almost ubiquitous signalling system involved in the control of cell fate. Recent studies have investigated the possibility that drugs targeting the endocannabinoid system might be used to retard or block cancer growth.

The endocannabinoids have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell signalling pathways. Therefore, the present review indicated that cannabinoids exert their anti-cancer effects in a number of ways and in a variety of tissues.

• Triggering cell death, through a mechanism called apoptosis
• Stopping cells from dividing
• Preventing new blood vessels from growing into tumours
• Reducing the chances of cancer cells spreading through the body, by stopping cells from moving or invading neighbouring tissue
• Speeding up the cell’s internal ‘waste disposal machine’ – a process known as autophagy – which can lead to cell death

Furthermore, the novel therapeutic application of cannabinoids in cancer disease, described here, strongly support the idea that cannabinoids may induce benefical effect in cancer treatment.”

http://www.oatext.com/novel-therapeutic-applications-of-cannabinoids-in-cancer-disease.php

Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.

May 25, 2018, 5:00 am

≫ Next: Cannabis for the Management of Cancer Symptoms: THC Version 2.0?

≪ Previous: Novel therapeutic applications of cannabinoids in cancer disease

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“Anandamide is a lipid neurotransmitter derived from arachidonic acid, a polyunsaturated fatty acid.

The chemical differences between anandamide and arachidonic acid result in a slightly enhanced solubility in water and absence of an ionisable group for the neurotransmitter compared with the fatty acid. In this review, we first analyze the conformational flexibility of anandamide in aqueous and membrane phases. We next study the interaction of the neurotransmitter with membrane lipids and discuss the molecular basis of the unexpected selectivity of anandamide for cholesterol and ceramide from among other membrane lipids.

We show that cholesterol behaves as a binding partner for anandamide, and that following an initial interaction mediated by the establishment of a hydrogen bond, anandamide is attracted towards the membrane interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the apolar membrane milieu.

The complex is then directed to the anandamide cannabinoid receptor (CB1) which displays a high affinity binding pocket for anandamide. We propose that cholesterol may regulate the entry and exit of anandamide in and out of CB1 by interacting with low affinity cholesterol recognition sites (CARC and CRAC) located in transmembrane helices.

The mirror topology of cholesterol binding sites in the seventh transmembrane domain is consistent with the delivery, extraction and flip-flop of anandamide through a coordinated cholesterol-dependent mechanism. The binding of anandamide to ceramide illustrates another key function of membrane lipids which may occur independently of protein receptors.

Interestingly, ceramide forms a tight complex with anandamide which blocks the degradation pathway of both lipids and could be exploited for anti-cancer therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/29789479

http://www.mdpi.com/2218-273X/8/2/31

“The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20983/

“The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774787/

Cannabis for the Management of Cancer Symptoms: THC Version 2.0?

May 26, 2018, 5:25 am

≫ Next: Involvement of the CB2 cannabinoid receptor in cell growth inhibition and G0/G1 cell cycle arrest via the cannabinoid agonist WIN 55,212-2 in renal cell carcinoma.

≪ Previous: Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.

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“The landscape of medical cannabis is rapidly expanding. Cannabis preparations have been used in medicine for millennia, and now there is a strong renaissance in the study of their therapeutic properties.

The vast majority of controlled clinical trials that support the medical use of what is commonly known as “cannabis” or “marijuana” have actually been conducted with purified cannabinoids or a single extract of Cannabis sativa that contains an equimolecular proportion of Δ⁹-THC and CBD.

Based on these studies, THC/dronabinol (Marinol) and its synthetic analogue nabilone (Cesamet), as well as nabiximols (Sativex), are already approved by several regulatory agencies, including FDA, Health Canada, and EMA, as antiemetic, anticachexic, analgesic, or antispastic medicines.

This study provides a precious piece of information on the use of medical cannabis for the management of cancer symptoms.”

https://www.liebertpub.com/doi/10.1089/can.2018.0009

Involvement of the CB2 cannabinoid receptor in cell growth inhibition and G0/G1 cell cycle arrest via the cannabinoid agonist WIN 55,212-2 in renal cell carcinoma.

May 26, 2018, 5:35 am

≫ Next: ∆9-tetrahydrocannabinol inhibits epithelial-mesenchymal transition and metastasis by targeting matrix metalloproteinase-9 in endometrial cancer.

≪ Previous: Cannabis for the Management of Cancer Symptoms: THC Version 2.0?

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“The anti-tumor properties of cannabinoids have been investigated in many in vitro and in vivo studies. Many of these anti-tumor effects are mediated via cannabinoid receptor types 1 and 2 (CB₁ and CB₂), comprising the endocannabinoid system (ECS).

In this study, we investigated the ECS based on CB ₁ and CB ₂ receptor gene and protein expression in renal cell carcinoma (RCC) cell lines. In view of their further use for potential treatments, we thus investigated the roles of CB₁ and CB₂ receptors in the anti-proliferative action and signal transduction triggered by synthetic cannabinoid agonists [such as JWH-133 and WIN 55,212-2 (WIN-55)] in RCC cell lines.

RESULTS:

The CB1 and CB2 genes expression was shown by real-time PCR and flow cytometric and western blot analysis indicating a higher level of CB₂ receptor as compared to CB₁ in RCC cells. Immunocytochemical staining also confirmed the expression of the CB₁ and CB₂ proteins. We also found that the synthetic cannabinoid agonist WIN-55 exerted anti-proliferative and cytotoxic effects by inhibiting the growth of RCC cell lines, while the CB₂ agonist JWH-133 did not. Pharmacologically blocking the CB1 and CB2 receptors with their respective antagonists SR141716A and AM-630, followed by the WIN-55 treatment of RCC cells allowed uncovering the involvement of CB2, which led to an arrest in the G0/G1 phase of the cell cycle and apoptosis.

CONCLUSIONS:

This study elucidated the involvement of CB₂ in the in vitro inhibition of RCC cells, and future applications of CB₂agonists in the prevention and management of RCC are discussed.

In summary, our study shows the involvement of CB₂ receptor in the in vitro inhibition of RCC cells. This knowledge will be useful to unravel the future applications of CB₂receptor and its agonists in the prevention and management of RCC.”

 https://www.ncbi.nlm.nih.gov/pubmed/29792186

https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4496-1

∆9-tetrahydrocannabinol inhibits epithelial-mesenchymal transition and metastasis by targeting matrix metalloproteinase-9 in endometrial cancer.

May 30, 2018, 5:08 am

≫ Next: The role of lipid signaling in the progression of malignant melanoma.

≪ Previous: Involvement of the CB2 cannabinoid receptor in cell growth inhibition and G0/G1 cell cycle arrest via the cannabinoid agonist WIN 55,212-2 in renal cell carcinoma.

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“Limited therapeutic interventions are clinically available for treating aggressive endometrial cancer (EC). Therefore, effective therapies are urgently required.

Therefore, the present study investigated the role of ∆⁹-tetrahydrocannabinol (THC), which is reported to impact proliferative and migratory activities during impairment of cancer progression.

In the present study, cell migration in response to THC was measured using transwell assays. Using western blot analysis, the levels of cannabinoid receptors in EC tissues were detected and pathways leading to the inhibition of cell migration by THC on human EC cells were determined.

Results suggested that cannabinoid receptors were highly expressed in EC tissues.

Furthermore, THC inhibited EC cell viability and motility by inhibiting epithelial-mesenchymal transition (EMT) and downregulating matrix metalloproteinase-9 (MMP-9) gene expression in aggressive human EC cells.

The results have the potential to promote the development of novel compounds for the treatment of EC metastasis. The present findings suggest that THC may inhibit human EC cell migration through regulating EMT and MMP-9 pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/29805589

https://www.spandidos-publications.com/10.3892/ol.2018.8407

The role of lipid signaling in the progression of malignant melanoma.

May 30, 2018, 6:55 am

≫ Next: Medical Oncologists’ Beliefs, Practices, and Knowledge Regarding Marijuana Used Therapeutically: A Nationally Representative Survey Study

≪ Previous: ∆9-tetrahydrocannabinol inhibits epithelial-mesenchymal transition and metastasis by targeting matrix metalloproteinase-9 in endometrial cancer.

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“In the past decades, a vast amount of data accumulated on the role of lipid signaling pathways in the progression of malignant melanoma, the most metastatic/aggressive human cancer type. Genomic studies identified that PTEN loss is the leading factor behind the activation of the PI3K-signaling pathway in melanoma, mutations of which are one of the main resistance mechanisms behind target therapy failures. On the other hand, illegitimate expressions of megakaryocytic genes p12-lipoxyganse, cyclooxygenase-2, and phosphodiestherase-2/autotaxin (ATX) are mostly involved in the regulation of motility signaling in melanoma through various G-protein-coupled bioactive lipid receptors. Furthermore, endocannabinoid signaling can also be a novel paracrine survival factor in melanoma. Last but not least, prenylation inhibitors acting even on mutated small GTP-ases, such as NRAS of melanoma may offer novel therapeutic opportunities. As regards melanoma, the most effective therapy nowadays is immunotherapy, with the resistance mechanisms also possibly involving the lipid signaling activities of melanoma cells, which further supports the idea of their being therapeutic targets.”

 https://www.ncbi.nlm.nih.gov/pubmed/29808460

https://link.springer.com/article/10.1007%2Fs10555-018-9729-x

Medical Oncologists’ Beliefs, Practices, and Knowledge Regarding Marijuana Used Therapeutically: A Nationally Representative Survey Study

May 31, 2018, 10:26 am

≫ Next: Anti-Tumorigenic Properties of Omega-3 Endocannabinoid Epoxides.

≪ Previous: The role of lipid signaling in the progression of malignant melanoma.

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“Although almost every state medical marijuana (MM) law identifies cancer as a qualifying condition, little research supports MM’s use in oncology. We hypothesized that the discrepancy between these laws and the scientific evidence base poses clinical challenges for oncologists. Oncologists’ beliefs, knowledge, and practices regarding MM were examined in this study.

Methods

In November 2016, we mailed a survey on MM to a nationally-representative, random sample of 400 medical oncologists. Main outcome measures included whether oncologists reported discussing MM with patients, recommended MM clinically in the past year, or felt sufficiently informed to make such recommendations. The survey also queried oncologists’ views on MM’s comparative effectiveness for several conditions (including its use as an adjunct to standard pain management strategies) and its risks compared with prescription opioids. Bivariate and multivariate analyses were performed using standard statistical techniques.

Results

The overall response rate was 63%. Whereas only 30% of oncologists felt sufficiently informed to make recommendations regarding MM, 80% conducted discussions about MM with patients, and 46% recommended MM clinically. Sixty-seven percent viewed it as a helpful adjunct to standard pain management strategies, and 65% thought MM is equally or more effective than standard treatments for anorexia and cachexia.

Conclusion

Our findings identify a concerning discrepancy between oncologists’ self-reported knowledge base and their beliefs and practices regarding MM. Although 70% of oncologists do not feel equipped to make clinical recommendations regarding MM, the vast majority conduct discussions with patients about MM and nearly one-half do, in fact, recommend it clinically. A majority believes MM is useful for certain indications. These findings are clinically important and suggest critical gaps in research, medical education, and policy regarding MM.”

http://ascopubs.org/doi/10.1200/JCO.2017.76.1221

“Survey: Oncologists Believe Medical Marijuana to be Equally or More Effective Than Conventional Cancer Treatments”  http://www.thedailychronic.net/2018/90645/survey-oncologists-believe-medical-cannabis-equally-effective-conventional-treatments/

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Anti-Tumorigenic Properties of Omega-3 Endocannabinoid Epoxides.

June 2, 2018, 5:12 am

≫ Next: The importance of 15-lipoxygenase inhibitors in cancer treatment.

≪ Previous: Medical Oncologists’ Beliefs, Practices, and Knowledge Regarding Marijuana Used Therapeutically: A Nationally Representative Survey Study

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“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

The importance of 15-lipoxygenase inhibitors in cancer treatment.

June 9, 2018, 5:52 am

≫ Next: Assessment of Cannabinoids Agonist and Antagonist in Invasion Potential of K562 Cancer Cells

≪ Previous: Anti-Tumorigenic Properties of Omega-3 Endocannabinoid Epoxides.

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“Cancer-targeted therapy is an expanding and successful approach in treatment of many types of cancers. One of the main categories of targeted therapy is use of small molecule inhibitors. 15-Lipoxygenase (15-LOX) is an enzyme which reacts with polyunsaturated fatty acids and produces metabolites that are implicated in many important human diseases, such as cancer.

Considering the role of 15-LOX (mainly 15-LOX-1) in the progression of some cancers, the discovery of 15-LOX inhibitors could potentially lead to development of novel cancer therapeutics and it can be claimed that 15-LOX inhibitors might be suitable as chemotherapy agents in the near future.

This article reviews relevant publications on 15-LOX inhibitors with focus on their anticancer activities in vitro and in vivo. Many 15-LOX inhibitors have been reported for which separate studies have shown their anticancer activities. This review paves the way to further explore the mechanism of their antiproliferative effects via 15-LOX inhibition.”

 https://www.ncbi.nlm.nih.gov/pubmed/29882120

https://link.springer.com/article/10.1007%2Fs10555-018-9738-9

“Cannabidiol-2′,6′-Dimethyl Ether, a Cannabidiol Derivative, Is a Highly Potent and Selective 15-Lipoxygenase Inhibitor”  http://dmd.aspetjournals.org/content/37/8/1733.long

“Δ9-tetrahydrocannabinol and its major metabolite Δ9-tetrahydrocannabinol-11-oic acid as 15-lipoxygenase inhibitors.”  https://www.ncbi.nlm.nih.gov/pubmed/20891010

Assessment of Cannabinoids Agonist and Antagonist in Invasion Potential of K562 Cancer Cells

June 10, 2018, 4:06 am

≫ Next: Appraising the “entourage effect”: antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer.

≪ Previous: The importance of 15-lipoxygenase inhibitors in cancer treatment.

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“The prominent hallmark of malignancies is the metastatic spread of cancer cells. Recent studies have reported that the nature of invasive cells could be changed after this phenomenon, causing chemotherapy resistance.

It has been demonstrated that the up-regulated expression of matrix metalloproteinase (MMP) 2/MMP-9, as a metastasis biomarker, can fortify the metastatic potential of leukemia.

Furthermore, investigations have confirmed the inhibitory effect of cannabinoid and endocannabinoid on the proliferation of cancer cells in vitro and in vivo.

Our findings clarifies that CB1 receptors are responsible for anti-invasive effects in the K562 cell line.”

https://www.ncbi.nlm.nih.gov/pubmed/29883990

Appraising the “entourage effect”: antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer.

June 26, 2018, 3:13 am

≫ Next: GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol.

≪ Previous: Assessment of Cannabinoids Agonist and Antagonist in Invasion Potential of K562 Cancer Cells

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“Breast cancer is the second leading cause of death among women. Although early diagnosis and development of new treatments have improved their prognosis, many patients present innate or acquired resistance to current therapies. New therapeutic approaches are therefore warranted for the management of this disease.

Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer. Most of these studies have been conducted with pure compounds, mainly Δ⁹-tetrahydrocannabinol (THC).

The cannabis plant, however, produces hundreds of other compounds with their own therapeutic potential and the capability to induce synergic responses when combined, the so-called “entourage effect”.

Here, we compared the antitumor efficacy of pure THC with that of a botanical drug preparation (BDP). The BDP was more potent than pure THC in producing antitumor responses in cell culture and animal models of ER+/PR+, HER2+ and triple-negative breast cancer. This increased potency was not due to the presence of the 5 most abundant terpenes in the preparation.

While pure THC acted by activating cannabinoid CB₂ receptors and generating reactive oxygen species, the BDP modulated different targets and mechanisms of action. The combination of cannabinoids with estrogen receptor- or HER2-targeted therapies (tamoxifen and lapatinib, respectively) or with cisplatin, produced additive antiproliferative responses in cell cultures. Combinations of these treatments in vivo showed no interactions, either positive or negative.

Together, our results suggest that standardized cannabis drug preparations, rather than pure cannabinoids, could be considered as part of the therapeutic armamentarium to manage breast cancer.”

 https://www.ncbi.nlm.nih.gov/pubmed/29940172

GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol.

June 27, 2018, 4:06 am

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“The G protein-coupled receptors 3, 6, and 12 (GPR3, GPR6, and GPR12) comprise a family of closely related orphan receptors with no confirmed endogenous ligands. These receptors are constitutively active and capable of signaling through G protein-mediated and non-G protein-mediated mechanisms. These orphan receptors have previously been reported to play important roles in many normal physiological functions and to be involved in a variety of pathological conditions.

Although they are orphans, GPR3, GPR6, and GPR12 are phylogenetically most closely related to the cannabinoid receptors. Using β-arrestin2 recruitment and cAMP accumulation assays, we recently found that the nonpsychoactive phytocannabinoid cannabidiol (CBD) is an inverse agonist for GPR3, GPR6, and GPR12.

This discovery highlights these orphan receptors as potential new molecular targets for CBD, provides novel mechanisms of action, and suggests new therapeutic uses of CBD for illnesses such as Alzheimer’s disease, Parkinson’s disease, cancer, and infertility. Furthermore, identification of CBD as a new inverse agonist for GPR3, GPR6, and GPR12 provides the initial chemical scaffolds upon which potent and efficacious agents acting on these receptors can be developed, with the goal of developing chemical tools for studying these orphan receptors and ultimately new therapeutic agents.”

https://www.ncbi.nlm.nih.gov/pubmed/29941868

https://www.nature.com/articles/s41401-018-0031-9