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

Oncology Clinicians and the Minnesota Medical Cannabis Program: A Survey on Medical Cannabis Practice Patterns, Barriers to Enrollment, and Educational Needs.

Cannabis and Cannabinoid Research cover image

“Medical cannabis has been available in the State of Minnesota since July 2015 through the Minnesota Medical Cannabis Program (MMCP).

Objectives: Our study aimed to delineate oncology providers’ views on medical cannabis, identify barriers to patient enrollment, and assess clinicians’ interest in a clinical trial of medical cannabis in patients with stage IV cancer.

Results: Of the 529 eligible survey participants, 153 (29%) responded to our survey; 68 respondents were registered with the MMCP. Most identified themselves as a medical oncologist or medical oncology nurse practitioner/physician assistant (n=125, 82%), and most practiced in a community setting (n=102, 67%). Overall, 65% of respondents supported the use of medical cannabis. Perceived cost and inadequate research were the highest barriers to MMCP patient enrollment. The lowest barriers included lack of health group support for allowing certification of patients and risk of social stigma. Of all respondents, 36% lacked confidence in discussing the risks and benefits of medical cannabis, and 85% wanted more education.

Conclusions: Although support for cannabis use in the cancer setting is growing, significant barriers remain. This study illustrates a clear need to give clinicians both data and education to guide their discussions about the benefits, risks, and cost considerations of using medical cannabis for cancer-related symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/30426072

https://www.liebertpub.com/doi/10.1089/can.2018.0029

Synthetic cannabinoids nano-micelles for the management of triple negative breast cancer.

 Journal of Controlled Release

“Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with poor prognosis and inadequate therapeutic outcome. This contribution reports the use of a cannabinoid derivative, WIN55,212-2 (WIN) on the growth of TNBC in a 4T1 syngeneic mouse model.

To reduce the well-known psychoactive side effects of cannabinoids, we prepared a nanomicellar formulation of WIN (SMA-WIN). In vivo biodistribution, in silico ADME predictions, anticancer activity, and psychoactive effect of WIN and SMA-WIN studies suggest that SMA-WIN formulation can reduce to greater extent tumor growth with milder psychoactive side effects when compared to free drug.

Finally, the effects of WIN and SMA-WIN in combination with doxorubicin (Doxo), an established chemotherapeutic agent for the treatment of TNBC, were investigated in vitro and in vivo. SMA-WIN in combination with Doxo showed therapeutic efficacy and was able to reduce the tumor volume of TNBC murine model drastically. Moreover, SMA-WIN, while favoring drug tumor accumulation, minimized the adverse psychoactive effects that have impeded the use of this agent in the clinic.

To our knowledge, this is the first report for the assessment of cannabinoid nanoparticles in vivo for the treatment of TNBC and its enhanced anticancer effect at low doses with Doxo. These findings suggest a new therapeutic strategy in the management of TNBC.”

https://www.ncbi.nlm.nih.gov/pubmed/30367922

https://www.sciencedirect.com/science/article/pii/S0168365918306114?via%3Dihub

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.”

Medical Cannabis Use by Hodgkin Lymphoma Patients: Experience of a Single Center.

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“Hodgkin lymphoma (HL) is one of the most curable malignancies. Despite its effectiveness, chemotherapy is often associated with adverse events (AEs) such as nausea, anorexia, and impairment of general well-being.

Our objective was to assess the extent of medical cannabis use among HL patients and evaluate its efficacy in controlling chemotherapy-related AEs.

Cannabis users reported improvement in pain, general well-being, appetite, and nausea in 94, 87, 82, and 79% of cases, respectively. Importantly, 81.5% reported a high overall efficacy of cannabis in relieving symptoms. AEs related to cannabis use itself were mild.

Thus, medical cannabis use is prevalent in this HL cohort, and appears to be effective in ameliorating chemotherapy-related AEs.”

https://www.ncbi.nlm.nih.gov/pubmed/30343297

https://www.karger.com/Article/Abstract/493567

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

At 70, Singer Olivia Newton-John​ Using Cannabis To Treat Cancer.

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“At 70, Singer Olivia Newton-John​ Using Cannabis To Treat Cancer. Olivia Newton-John says she has been diagnosed with cancer for the third time in three decades. Newton-John says she’s “treating it naturally and doing really well.” The “Grease” star says she is taking cannabis oil, made from marijuana her husband John Easterling grows on their ranch in Santa Barbara. She said, “I believe I will win over it.”” https://sanfrancisco.cbslocal.com/2018/09/10/olivia-newton-john-cannabis-cancer/

“Grease star Olivia Newton-John is battling her breast cancer with cannabis. Grease star Olivia Newton-John is offering an update on her third battle with cancer and revealing how cannabis has become a key component in her treatment plan.”   http://www.digitalspy.com/showbiz/news/a865881/grease-olivia-newton-john-battling-breast-cancer-with-cannabis/

Olivia Newton-John Says She’s Managing Breast Cancer with Cannabis. Newton-John explained that she uses cannabis oil to treat the pain and help her sleep, much of which her husband John Easterling (who runs Amazon Herb Company) grows for her. “I’m very lucky that I live in a state where it’s legal and that I have a husband who is a plant medicine man,” she said. “How lucky is that?” Newton-John also advocated for legalizing cannabis in her home country of Australia, adding, “My dream is that it will be available to all the cancer patients or people going through cancer or any kind of disease that causes pain.” Newton-John turns 70 on September 26.” http://exclaim.ca/music/article/olivia_newton-john_says_shes_managing_breast_cancer_with_cannabis

“Olivia Newton-John diagnosed with cancer for a third time but believes she ‘will win’ health battle with homegrown cannabis treatment. The Grease actress is using homegrown cannabis as part of her treatment to fight the disease. She drinks a cannabis mixture made by her herbalist husband to control the illness.” https://www.mirror.co.uk/3am/celebrity-news/olivia-newton-john-diagnosed-cancer-13220595

“Olivia Newton-John uses medical marijuana to treat cancer”  https://www.buzz.ie/celebs/olivia-newton-john-drinks-cannabis-extract-numb-pain-cancer-253796

“Olivia Newton-John reveals marijuana helping her beat cancer”   http://www.9news.com.au/national/2017/09/03/08/58/olivia-newton-john-backs-medicinal-cannabis

“Olivia Newton-John’s cancer battle is going well… Thanks to cannabis oil!”  https://closeronline.co.uk/celebrity/news/olivia-newton-john-daughter-chloe-lattanzi-cannabis-oil-cancer/ 

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Olivia Newton-John ‘Feeling Great’ as Source Denies ‘False’ Report Her Cancer Has Spread Further. “This is just false,” a source close to Newton-John tells PEOPLE. “She’s feeling and looking great. Everything that’s being reported about her diagnosis is the same news she released last year.” https://people.com/music/olivia-newton-john-denies-false-report-cancer-spread/

“Olivia Newton-John Reveals Secret Cancer Battle in 2013: ‘I Just Decided to Keep It to Myself.” Last year, Newton-John announced she’d been diagnosed with stage 4 breast cancer that had metastasized to her back, but the 69-year-old actress has been treating the illness with natural wellness therapies, including medicinal marijuana. A source close to Newton-John tells PEOPLE that she’s been feeling fine and healthy as of late.” https://people.com/music/olivia-newton-john-secret-cancer-battle-decided-keep-myself/

Olivia Newton-John: It’s not just cancer sufferers needing help, carers do too. The mum-of-one discovered she had a tumour in the base of her spine last year. She had previously overcome breast cancer in 1992 after undergoing surgery and chemo, before secretly beating the disease again in 2013. Praising both husband John and her daughter Chloe, Olivia said: “Of course they’ve been a huge support, I think it’s hard for people on the outside – the care takers – because they have to be taken care of too sometimes, because it is hard for them.” John grows cannabis plants for Olivia, as she has chosen natural therapies such as cannabis oil to help ease her pain from the disease, instead of opioids and other drugs such as chemo this time round. He grows the plants in California where the couple live, as it is legal there.” https://startsat60.com/entertainment/tv-movies/olivia-newton-john-cancer-sufferers-carers-husband-john-help

“‘I use cannabis’: Olivia Newton-John talks cancer treatment” https://startsat60.com/health/i-use-cannabis-olivia-newton-john-opens-up-on-cancer-treatment

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“Olivia Newton-John Is Using Cannabis Oil To Treat Her Cancer”  https://www.inverse.com/article/32780-cannabis-oil-cancer-treatment-cannabinoid-chemotherapy

“Olivia Newton John’s cannabis oil for cancer treatment” https://www.msn.com/en-nz/health/medical/olivia-newton-johns-cannabis-oil-for-cancer-treatment/ar-AAoTvE3

“‘I believe I will win’: Olivia Newton-John, 69, reveals the tragic cancer diagnosis she kept secret… as she fights the disease for a third time with the help of her husband” https://www.dailymail.co.uk/tvshowbiz/article-6148177/Olivia-Newton-John-69-reveals-tragic-cancer-diagnosis-kept-secret.html

“Olivia’s husband grows her medical marijuana”  https://au.be.yahoo.com/entertainment/celebrity/a/37038356/john-easterling-home-grows-olivia-newton-johns-medical-marijuana/

“Olivia Newton-John Admits to Using Home-Grown Medical Marijuana to Battle Cancer” http://popculture.com/2017/09/11/olivia-newton-john-medical-marijuana-breast-cancer/

“Olivia Newton-John Reveals She Was Unable to Walk After Cancer Relapse – and She’s Using Marijuana to Ease Pain. The 68-year-old said that the “hardest thing” has been her pain level, admitting that trying to do shows was “really agonizing.” Now, she’s been treating the pain with medical marijuana her husband John Easterling grows. “I’ll be fine,” said Newton-John.” https://people.com/music/olivia-newton-john-cancer-update-couldnt-walk-australian-60-minutes/

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“Olivia Newton-John on Being a Cancer ‘Thriver’ and Using Weed to Cope with Her Relapse: It’s a ‘Healing Plant’. The actress also shared that she’s been treating the pain with medical marijuana her husband John Easterling grows. “People have this vision from the ’60s of people just sitting around and getting stoned,” she said. “It’s not about that. This plant is a healing plant. I think we need to change the vision of what it is because it helped me greatly and it helps with pain and inflammation.”” https://people.com/music/olivia-newton-john-cancer-relapse-weed/

Olivia Newton-John reveals she is on medical cannabis for cancer” https://www.dailymail.co.uk/health/article-6171365/Olivia-Newton-John-reveals-medical-cannabis-breast-cancer.html

“‘It’s a magical miracle plant:’ Olivia Newton-John reveals husband John Easterling grows marijuana to aid her breast cancer battle” https://www.dailymail.co.uk/tvshowbiz/article-4869940/Olivia-Newton-John-benefits-medical-marijuana.html

“‘It’s really important and should be available’: Olivia Newton-John speaks about how ‘medical cannabis’ is helping her beat breast cancer” https://www.dailymail.co.uk/tvshowbiz/article-4846664/Olivia-Newton-John-talks-cannabis-use-time.html

“Olivia Newton-John voices her support for medical marijuana after revealing her husband grows the plant to aid her breast cancer battle” https://www.dailymail.co.uk/tvshowbiz/article-4891760/Olivia-Newton-John-voices-support-medical-marijuana.html

“Let’s Get Physical! Olivia Newton-John beams in green as she dazzles Melbourne crowds at charity walk to raise funds for her cancer research centre… after speaking candidly about her attempts to ‘win over’ the disease” https://www.dailymail.co.uk/tvshowbiz/article-6172857/Olivia-Newton-John-beams-green-dazzles-crowds-cancer-research-charity-walk.html

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“‘Medical cannabis has helped me a lot’: Olivia Newton-John speaks candidly about the ‘healing remedies’ that have helped CURE her pain during her agonising cancer battle” https://www.dailymail.co.uk/tvshowbiz/article-5181401/Olivia-Newton-John-speaks-candidly-medical-cannabis.html

“Olivia Newton-John using cannabis oil as she battles cancer for the third time”  https://www.hellomagazine.com/healthandbeauty/health-and-fitness/2018091162192/olivia-newton-john-using-cannabis-oil-battles-cancer-third-time/

“Olivia Newton-John Says She’s Winning Her Third Cancer Battle And Feels Great” https://www.closerweekly.com/posts/olivia-newton-john-says-shes-winning-her-third-cancer-battle-and-feels-great
“Olivia leads the biggest ever Wellness Walk and Research Run!” https://www.onjcancercentre.org/news/article/2018/09/18/biggest-ever-wellness-walk-and-research-run
“Well over half a million dollars has been raised so far and while the event itself is over for this year, fundraising is still open until the 30 September. You can continue to support family and friends by donating to their page, or you can donate to Olivia’s page here: https://secure.artezpacific.com/registrant/FundraisingPage.aspx?registrationID=1213890&langPref=en-CA

“The Olivia Newton-John Cancer Wellness & Research Centre is at the frontier of cancer medicine, with over 200 ongoing clinical trials.” https://www.onjcancercentre.org/patients-family/clinical-trials

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http://www.thctotalhealthcare.com/olivia-newton-john-champions-the-use-of-magical-miracle-medicinal-cannabis/

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

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

Care After Chemotherapy: Peripheral Neuropathy, Cannabis for Symptom Control, and Mindfulness.

ASCO Educational Book

“As cancer therapies improve, patients are living longer. With these improvements in therapy comes a responsibility to optimize patients’ quality of life during cancer therapy and beyond. This report reviews three timely and important topics.

The first section reviews the mechanism underlying chemotherapy-induced peripheral neuropathy and evaluates the evidence for interventions to prevent and treat peripheral neuropathy. It also provides a framework for approaching the diagnosis and management of this common and bothersome side effect.

The second section addresses the controversial but effective use of cannabinoids for cancer and chemotherapy symptoms. Although clinical trials are difficult to conduct because of the political and social stigma of this class of drugs, this review provides evidence of the efficacy of cannabinoids for treatment of pain and nausea.

The last section addresses the mind-body connection, with a focus on the negative emotions patients with cancer often experience. This section assesses the literature regarding mindfulness-based programs to improve cancer-related stress. These three topics may appear unrelated, but all address one common goal: treating the body and the mind to optimize quality of life during and after cancer therapy.”

“Although commercially available dronabinol is not superior to other antiemetics and oromucosal nabiximols is not very effective for treating cancer pain, cannabis has been shown to be effective for treating pain and may help patients reduce opioid intake.”