Modulation of the Endocannabinoid System as a Potential Anticancer Strategy.

 Image result for frontiers in pharmacology“Currently, the involvement of the endocannabinoid system in cancer development and possible options for a cancer-regressive effect of cannabinoids are controversially discussed. In recent decades, a number of preclinical studies have shown that cannabinoids have an anticarcinogenic potential. Therefore, especially against the background of several legal simplifications with regard to the clinical application of cannabinoid-based drugs, an extended basic knowledge about the complex network of the individual components of the endocannabinoid system is required. The canonical endocannabinoid system consists of the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol as well as the Gi/o protein-coupled transmembrane cannabinoidreceptors CB1 and CB2. As a result of extensive studies on the broader effect of these factors, other fatty acid derivatives, transmembrane and intracellular receptors, enzymes and lipid transporters have been identified that contribute to the effect of endocannabinoids when defined in the broad sense as “extended endocannabinoid system.” Among these additional components, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid-binding protein family, additional cannabinoid-activated G protein-coupled receptors such as GPR55, members of the transient receptor family, and peroxisome proliferator-activated receptors were identified as targets for possible strategies to combat cancer progression. Other endocannabinoid-related fatty acids such as 2-arachidonoyl glyceryl ether, O-arachidonoylethanolamine, N-arachidonoyldopamine and oleic acid amide showed an effect via cannabinoid receptors, while other compounds such as endocannabinoid-like substances exert a permissive action on endocannabinoid effects and act via alternative intracellular target structures. This review gives an overview of the modulation of the extended endocannabinoid system using the example of anticancer cannabinoid effects, which have been described in detail in preclinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31143113

“In addition to the palliative effects of cannabinoid compounds in cancer treatment, the endocannabinoid system provides several targets for systemic anticancer treatment. Accordingly, preclinical studies suggest cannabinoids inhibit cancer progression via inhibition of cancer cell proliferation, neovascularization, invasion and chemoresistance, as well as induction of apoptosis, autophagy and increase of tumor immune surveillance.”

https://www.frontiersin.org/articles/10.3389/fphar.2019.00430/full

Future Aspects for Cannabinoids in Breast Cancer Therapy.

ijms-logo

“Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients.

Additionally, they may decelerate tumor progression in breast cancer patients.

Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models.

The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way.

THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both.

In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway.

They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis.

Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor.

In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression.”

The onus of cannabinoids in interrupting the molecular odyssey of breast cancer: A critical perspective on UPRER and beyond.

Saudi Pharmaceutical Journal

“Cannabinoids, commonly used for medicinal and recreational purposes, consist of various complex hydrophobic molecules obtained from Cannabis sativa L. Acting as an inhibitory molecule; they have been investigated for their antineoplastic effect in various breast tumor models. Lately, it was found that cannabinoid treatment not only stimulates autophagy-mediated apoptotic death of tumor cells through unfolded protein response (UPRER) activated downstream effectors, but also imposes cell cycle arrest. The exploitation of UPRER tumors as such is believed to be a major molecular event and is therefore employed in understanding the development and progression of breast tumor. Simultaneously, the data on clinical trials following administration of cannabinoid is currently being explored to find its role not only in palliation but also in the treatment of breast cancer. The present study summarizes new achievements in understanding the extent of therapeutic progress and highlights recent developments in cannabinoid biology towards achieving a better cure of breast cancer through the exploitation of different cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/30976189

https://www.sciencedirect.com/science/article/pii/S1319016419300064?via%3Dihub

Characterization of Cancer-Induced Nociception in a Murine Model of Breast Carcinoma.

“Severe and poorly treated pain often accompanies breast cancer. Thus, novel mechanisms involved in breast cancer-induced pain should be investigated. Then, it is necessary to characterize animal models that are reliable with the symptoms and progression of the disease as observed in humans. Explaining cancer-induced nociception in a murine model of breast carcinoma was the aim of this study. 4T1 (104) lineage cells were inoculated in the right fourth mammary fat pad of female BALB/c mice; after this, mechanical and cold allodynia, or mouse grimace scale (MGS) were observed for 30 days. To determine the presence of bone metastasis, we performed the metastatic clonogenic test and measure calcium serum levels. At 20 days after tumor induction, the antinociceptive effect of analgesics used to relieve pain in cancer patients (acetaminophen, naproxen, codeine or morphine) or a cannabinoid agonist (WIN 55,212-2) was tested. Mice inoculated with 4T1 cells developed mechanical and cold allodynia and increased MGS. Bone metastasis was confirmed using the clonogenic assay, and hypercalcemia was observed 20 days after cells inoculation. All analgesic drugs reduced the mechanical and cold allodynia, while the MGS was decreased only by the administration of naproxen, codeine, or morphine. Also, WIN 55,212-2 improved all nociceptive measures. This pain model could be a reliable form to observe the mechanisms of breast cancer-induced pain or to observe the efficacy of novel analgesic compounds.”

https://www.ncbi.nlm.nih.gov/pubmed/30850915

https://link.springer.com/article/10.1007%2Fs10571-019-00666-8

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer.

 Proceedings of the National Academy of Sciences: 116 (6)

“Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted.

Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB2R. We show that HER2 physically interacts with CB2R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis.

The cannabinoid Δ9-tetrahydrocannabinol (THC) disrupts HER2-CB2R complexes by selectively binding to CB2R, which leads to (i) the inactivation of HER2 through disruption of HER2-HER2 homodimers, and (ii) the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CB2R transmembrane region 5 mimicked THC effects.

Together, these findings define HER2-CB2R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/30733293

https://www.pnas.org/content/early/2019/02/06/1815034116

“Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer” http://www.ncbi.nlm.nih.gov/pubmed/25855725
“Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer. 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

Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer.

 Related image“In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain.

The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety.

Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB1 and CB2.

CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ9-THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa, since it contains only few levels of Δ9-THC and high levels of CBD and related nonpsychoactive compounds.

In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials.

CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ9-THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models.

These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity.

In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ9-THC deprived hemp.”

https://www.ncbi.nlm.nih.gov/pubmed/30627539

https://www.hindawi.com/journals/bmri/2018/1691428/

Cannabidiolic Acid-Mediated Interference with AP-1 Transcriptional Activity in MDA-MB-231 Breast Cancer Cells.

 Image result for Nat Prod Commun journal

“We reported that cannabidiolic acid (CBDA), a non-psychotropic constituent of fiber-type cannabis plants, down-regulates the mRNA expression of cyclooxygenase-2 (COX-2) in highly aggressive MDA-MB-231 human breast cancer cells. However, the molecular mechanism(s) underlying the CBDA suppression of COX-2 have not yet been elucidated in detail. In MDA-MB-231 cells, COX-2 expression is known to be tightly regulated by the transcriptional activity of activator protein-I (AP-1), which is composed of a heterodimer of c-Fos and c-Jun. AP-1-mediated transcriptional activity was inhibited by CBDA in a dose-dependent manner. The expression of c-fos was maintained at markedly lower levels (0.035) than basal c-jun expression levels (1.0), implicating c- fos as a limiting factor in the regulation of COX-2. Analyses indicated that CBDA abrogated the expression of c-fos mRNA without affecting c-jun. Collectively, these results suggest that CBDA abolishes the expression of COX-2 by interfering with AP-I activity in MDA-MB3-231 cells.”

https://www.ncbi.nlm.nih.gov/pubmed/30496661

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

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/