Bone cell-autonomous contribution of type 2 cannabinoid receptor to breast cancer induced osteolysis.

“The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumour growth, bone remodelling and bone pain.

However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here, we found that the CB2 selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micro-molar concentrations…

When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands, depending upon cell type and concentration used.

We therefore conclude that both, CB2 selective activation and antagonism have potential efficacy in cancer associated bone disease but further studies are warranted and ongoing.”

Phytocannabinoids for Cancer Therapeutics: Recent Updates and Future Prospects.

“Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in traditional and recreational medicine.

The plant and constituents were central in the discovery of the endocannabinoid system, the most new target for drug discovery.

The endocannabinoid system includes two G protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana’s psychoactive principle ∆(9)-tetrahydrocannabinol (∆9-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the proteins for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

The endocannabinoid system has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer.

Targeting the CB1 receptors become a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzyme by phytocannabinoids obtained from non-cannabis plant lacking psychotropic adverse reactions has garnered interest in drug discovery.

These pCBs derived from plants beyond cannabis appear safe and effective with a wider access and availability.

In recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development in cancer therapeutics.

Several of them also target the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize, critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics.”

http://www.ncbi.nlm.nih.gov/pubmed/26179998

http://www.thctotalhealthcare.com/category/cancer/

Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor

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“We have previously shown that AEA exerts growth-suppressing effects on cholangiocarcinoma by inducing apoptosis.

At the time, we assumed that AEA was acting via a receptor-independent mechanism.

However, given the recent discovery and characterization of GPR55 as a novel AEA receptor, our data need to be reassessed to determine if GPR55 activation can decrease cholangiocarcinoma cell proliferation.

Thus, our aims are to determine if these AEA-mediated effects on cholangiocarcinoma cell growth can be attributed to the activation of GPR55.

This data represent the first evidence that GPR55 activation by anandamide can lead to the recruitment and activation of the Fas death receptor complex and that targeting GPR55 activation may be a viable option for the development of therapeutic strategies to treat cholangiocarcinoma.

In conclusion, we have clearly demonstrated a role for GPR55 in the antiproliferative effects of AEA in vivo andin vitro

Cholangiocarcinoma has a very poor prognosis and survival rate; therefore we propose that the development of novel therapeutic strategies that target GPR55 may prove beneficial for the treatment of this devastating disease.

Consistent with our observation that AEA has antiproliferative and pro-apoptotic properties, cannabinoids of various origins (endogenous, plant-derived or synthetic analogues) have been shown to suppress cancer cell growth in vitro as well as in vivo.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126905/

 

The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway.

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“Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options.

Marijuana and its derivatives have been used in medicine for many centuries.

…cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture and in laboratory animals.

Indeed, we have recently demonstrated that the endocannabinoid anandamide (AEA) has antiproliferative effects on cholangiocarcinoma cell lines in vitro via a cannabinoid receptor-independent pathway involving the stabilization of lipid raft-membrane structures and the recruitment of death-receptor complexes into the lipid rafts.

Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment.

The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.

We propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA, would prove beneficial for the treatment of this devastating disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2604798/

 

Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

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“Cholangiocarcinomas are devastating cancers of intrahepatic and extrahepatic origin that are increasing in both their worldwide incidence and mortality rates.

Conventional chemotherapy and radiation therapy are not effective in prolonging long-term survival; therefore it is important to understand the cellular mechanisms of cholangiocarcinoma cell growth with a view to develop novel chemopreventive strategies.

We have recently demonstrated that the endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) exert opposing effects on cholangiocarcinoma cell growth in vitro via cannabinoid receptor-independent mechanisms.

AEA increased presenilin 1 expression and recruitment into the γ-secretase complex whereas 2-AG increased expression and recruitment of presenilin 2.

The development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

We propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for the treatment of this devastating disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872061/

Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts.

The Journal of Biological Chemistry

“Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options…

Marijuana and its derivatives have been used in medicine for many centuries, and presently there is an emerging renaissance in the study of the therapeutic effects of cannabinoids…

In addition, cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture and in laboratory animals.

Modulation of the endocannabinoid system is being targeted to develop possible therapeutic strategies for a number of cancers; therefore, we evaluated the effects of the two major endocannabinoids, anandamide and 2-arachidonylglycerol, on numerous cholangiocarcinoma cell lines…

These findings suggest that modulation of the endocannabinoid system may be a target for the development of possible therapeutic strategies for the treatment of this devastating cancer.

Consistent with our observation that AEA has antiproliferative and proapoptotic properties, cannabinoids of various origins (endogenous, plant-derived, or synthetic analogues) have been shown to suppress cancer cell growth in vitro as well as in vivo.

In conclusion, we have clearly demonstrated opposing actions of the endocannabinoids AEA and 2-AG on cholangiocarcinoma cell proliferation and have shown that these actions are via a cannabinoid receptor-independent but lipid raft-mediated pathway. Furthermore we have shown that the antiproliferative/proapoptotic actions of AEA are mediated via an accumulation of ceramide and the recruitment of the Fas death receptor into the lipid rafts. Cholangiocarcinoma has a very poor prognosis and survival rate; therefore we propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA would prove beneficial for the treatment of this devastating disease.”

http://www.jbc.org/content/282/17/13098.long

The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration.

“Currently, only gemcitabine plus platinum demonstrates the considerable activity for cholangiocarcinoma.

The anticancer effect of Delta (9)-tetrahydrocannabinol (THC), the principal active component of cannabinoids has been demonstrated in various kinds of cancers.

We therefore evaluate the antitumor effects of THC on cholangiocarcinoma cells.

Both cholangiocarcinoma cell lines and surgical specimens from cholangiocarcinoma patients expressed cannabinoid receptors.

THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis.

THC also decreased actin polymerization and reduced tumor cell survival in anoikis assay. pMEK1/2 and pAkt demonstrated the lower extent than untreated cells.

Consequently, THC is potentially used to retard cholangiocarcinoma cell growth and metastasis.” http://www.ncbi.nlm.nih.gov/pubmed/19916793 

“Cholangiocarcinoma is an epithelial cell malignancy arising from varying locations within the biliary tree showing markers of cholangiocyte differentiation. The most contemporary classification based on anatomical location includes intrahepatic, perihilar, and distal cholangiocarcinoma… Understanding of cholangiocarcinoma biology, the oncogenic landscape of this disease, and its complex interaction with the tumour microenvironment could lead to optimum therapies with improvement in patient survival… Hopefully, personalised or precision medicine is in the near future for the treatment of cholangiocarcinoma” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069226/

 “Cholangiocarcinomas (bile duct cancers) are a heterogeneous group of malignancies arising from the epithelial cells of the intrahepatic, perihilar and extrahepatic bile ducts.”   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731530/

“Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy after hepatocellular cancer. CC accounts for approximately 10%-25% of all hepatobiliary malignancies. CC is a rare malignancy in Western countries, but more common in Asia. There are several established risk factors for CC, including parasitic infections, primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, and toxins. Other less-established potential risk factors include inflammatory bowel disease, hepatitis C virus, hepatitis B virus, cirrhosis, diabetes, obesity, alcohol drinking, tobacco smoking, and host genetic polymorphisms.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125451/

“Cholangiocarcinoma is a highly malignant cancer of the biliary tract with a poor prognosis, which often arises from conditions causing long-term inflammation, injury, and reparative biliary epithelial cell proliferation. Several conditions are known to be major risk factors for cancer in the biliary tract or gallbladder, including primary sclerosing cholangitis, liver fluke infection, pancreaticobiliary maljunction, and chemical exposure in proof-printing workers.”  http://www.ncbi.nlm.nih.gov/pubmed/24895231

http://www.thctotalhealthcare.com/category/cholangiocarcinoma/

The use of cannabinoids as anticancer agents.

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“It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumour growth in animal models of cancer.

Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death.

In addition, cannabinoids inhibit tumour angiogenesis and decrease cancer cell migration.

The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored.

In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.” http://www.ncbi.nlm.nih.gov/pubmed/26071989

“… cannabinoids have been shown to alleviate nausea and vomit induced by chemotherapy and several cannabinoid-based medicines [Marinol (THC) and Cesamet (nabilone, a synthetic analogue of THC)] are approved for this purpose. Cannabinoids also inhibit pain, and Sativex (a standardized cannabis extract) has been approved in Canada for the treatment of cancer-associated pain. Other potential palliative effects of cannabinoids in oncology include appetite stimulation and attenuation of wasting. In addition to these palliative actions of cannabinoids in cancer patients, THC and other cannabinoids exhibit antitumour effects in animal models of cancer… a large body of scientific evidences strongly support THC and other cannabinoid agonists exert anticancer actions in preclinical models of cancer… In conclusion there exist solid scientific evidences supporting that cannabinoids exhibit a remarkable anticancer activity in preclinical models of cancer. Since these agents also show an acceptable safety profile, clinical studies aimed at testing them as single agents or in combinational therapies are urgently needed.” http://www.sciencedirect.com/science/article/pii/S0278584615001190

Marijuana kills brain cancer, new study confirms

“The active molecules in cannabis kill brain cancer — another study has revealed.”

“Scientists using an extract of whole-plant marijuana rich in pot’s main psychoactive ingredient THC as well as cannabidiol (CBD) showed “dramatic reductions in tumor volumes” of a type of brain cancer.”  http://blog.sfgate.com/smellthetruth/2014/11/18/marijuana-kills-brain-cancer-new-study-confirms/

“Marijuana kills brain cancer, new study confirms. The active molecules in cannabis kill brain cancer — another study has revealed.” http://blog.seattlepi.com/marijuana/2014/11/18/marijuana-kills-brain-cancer-new-study-confirms/#13130101=0

“Marijuana Kills Brain Cancer Cells. Researchers have found that the THC in marijuana causes brain cancer cells to die in both mice and humans.”  http://www.nbcphiladelphia.com/news/health/Marijuana_Kills_Brain_Cancer_Cells_All__National_.html

“Marijuana Kills Brain Cancer, New Study Confirms” http://cancerguide.byethost8.com/marijuana-kills-brain-cancer-new-study-confirms-sfgate-blog/

http://www.thctotalhealthcare.com/category/brain-cancer/

Cannabisin B induces autophagic cell death by inhibiting the AKT/mTOR pathway and S phase cell cycle arrest in HepG2 cells.

“This study investigates the anticancer properties of cannabisin B, purified from hempseed hull, in HepG2 human hepatoblastoma cells.

The results indicate that cannabisin B significantly inhibited cell proliferation by inducing autophagic cell death rather than typical apoptosis.

Cell viability transiently increased upon the addition of a low concentration of cannabisin B but decreased upon the addition of high concentrations.

Cannabisin B-induced changes in cell viability were completely inhibited by pre-treatment with 3-methyladenine (3-MA), indicating that the induction of autophagy by cannabisin B caused cell death.

Additionally, cannabisin B induced S phase cell cycle arrest in a dose-dependent manner.

Moreover, cannabisin B was found to inhibit survival signaling by blocking the activation of AKT and down-stream targets of the mammalian target of rapamycin (mTOR).

These findings suggest that cannabisin B possesses considerable antiproliferative activity and that it may be utilised as a promising chemopreventive agent against hepatoblastoma disease.”

http://www.ncbi.nlm.nih.gov/pubmed/23411211

http://www.thctotalhealthcare.com/category/liver-cancer-2/