How Does Cannabis Kill Cancer Cells ? Part Two

by Jeffrey Dach MD

As described in part one, the cancer cell is a mutated, primitive cell that has lost the cell signalling mechanism for Programmed Cell Death.  Perhaps PCD (programmed cell death) has been intentionally silenced by the evil cancer cell.  If we could somehow restore and then trigger the pathways for programmed cell death in the cancer cells, we would have ourselves an exceptional cancer treatment.   This is the beauty of the phyto-cannabinoids, THC and CBD. which restore programmed cell death signalling in the cancer cells by utilizing whatever pathways are available.  If one pathway is blocked, the Cannabinoid signalling finds another pathway to terminate in apoptosis or programmed cell death of the cancer cell..

The “Whack-A Mole” Concept of Programmed Cell Death

This idea of switching among pathways,  depending on what is available, is perhaps best described as the “Whack-a-Mole” concept of programmed cell death.  Now we can understand why so many differing pathways are utilized by Cannabinoids in the various cancer models studied, all terminating at a common endpoint, programmed cell death (PCD).

Whack -A-Mole is the “the practice of repeatedly getting rid of something, only to have more of that thing appear”.  Above Left image courtesy of CitizenThymes.com

This article is part two, for part one click here.

Dr Manual Guzman and the Cannabinoid Signalling Group in Madrid Spain

Dr Manuel Guzman has devoted his career to the anti-cancer activity of phyto-cannabinoids such as THC (Tetra-Hydo-Cannabinol) and CBD (CannaBiDiol). Left Image courtesy of Manuel Guzman.

Cannabinoids Induce Programmed Cells Death

In an editorial in 2012, Dr Guzman says the anti-cancer effects of Cannabinoids are due to their ability to induce Programmed Cell Death (PCD, apoptosis).  In addition, Dr Guzman cites animal experiments showing cannabinoids inhibit new vessel growth in cancerous tissue, block cancer cell invasion of surrounding tissues and block metastasis spread of cancer cells.(1)

Accumulation of Ceramide in Glioma Cells

Dr Guzman has studied Glioma cells extensively,. These are the brain cancer cells, and he reports that THC and other cannabinoids induce programmed cell death (apoptosis) in Glioma cells.  The mechanism elucidated so far, is the intra-cellular accumulation of the death signal molecule ceramide, which is triggered by activation of endocannabinoid receptors,CB1 and CB2.(1)  Ceramide accumulation in the cell targets the mitochondria, causing autophagosomes to attach to the mitochondria which then undergo mitophagy, (ie they “eat themselves”). Electron microscope studies show loss of mitochondrial inner membranes with ballooning and vacuolization of the mitochondria. As you might expect, this leads to loss of mitochondrial function, and programmed cell death.

CBD- Independent of Cannabinoid Receptors

Cannabidiol, CBD, the non-psychoactive component of cannabis, appears to cause programmed cell death in a manner independent of the CB1 and CB2 receptor system.  As reported by McAllister’s group, the anti-cancer effect of CBD seems to be related to downregulation of the ID-1 gene through the ERK/MAPK pathway.(1)

The Mitochondrial “Governator”

A different CBD mechanism of Programmed Cell Death is described in a study by Rimmerman at Tel Aviv University.  This involves the VDAC, the Voltage Dependent Anion Channel in the mitochondrial membrane.  The VDAC is a key regulator of mitochondrial function  and has been dubbed “The Governator” of mitochondrial activity.

Dr.  Rimmerman at Tel Aviv University reported in 2013 that CBD acts directly on the VDAC, to open the channels and increase membrane permeability.(6)   This allows the release of Cytochrome C into the cytosol which then actives the Caspase proteolytic enzyme cascade, irreversibly triggering the intrinsic pathway for programmed cell death in cancer cells. The exact receptors have yet to be elucidated. (6)  Upper left image: Governator courtesy of Huffington Post.

NUPR, the Swiss Knife of Cancer – Stress Related Protein P8

Another possible mechanism for PCD is the P8 pathway.  The cannabinoid molecule, THC, upregulates expression of the stress-regulated protein p8 (also known as NUPR1), a transcriptional regulator which causes endoplasmic reticulum (ER) stress, and may trigger programmed cell death via the intrinsic mitochondrial pathway or by autophagy (the cell eats itself).(8)  The NUPR1 gene has been dubbed the Swiss Knife of Cancer.  This P8/NUPR1 pathway has been shown in glioma cells, pancreatic and hepatic cancer cells. (1,8)   Dr Guzman speculates that perhaps this pathway may serve as the main mechanism by which endocannabinoid receptor activation induces PCD, programmed cell death.(1) Left image swiss knife courtesy of wikimedia commons.

Selective for Cancer Cells – Leaving Normal Cells Unharmed

As mentioned above, THC and CBD are the two major anti-cancer cannabinoids used by the medical marijuana community.  These cannabinoids selectively target cancer cells for Programmed Cell Death, while sparing normal cells, which are left unaffected.  While considerable progress has been made on the molecular mechanism of programmed cell death in cancer cells, the precise mechanism for the sparing of normal cells, ie.”cancer cell selectivity” has yet to be elucidated.(1)

This type of selectivity is a rare and sought after feature, and as you might imagine, very beneficial for the cancer patient.  On the other hand, cytotoxic chemotherapy, the standard of care for cancer patients by the mainstream oncologist, has no selectivity and kills normal cells along with the cancer cells.  This lack of selectivity causes well known adverse side effects  of chemotherapy including nausea, vomiting, hair loss, chronic fatigue, anemia, neuropathy, etc.

Pilot Study in 9 Glioblastoma Patients

In 2006, Manuel Guzman’s group published their pilot study using THC infused directly into the brain tumor of 9 patients with recurrent malignant glioblastoma. (3)  The results of this pilot study were unimpressive.  At least the THC did no harm and was well tolerated.(3)  There may have been some benefit in two of the patients, and brain biopsy material could be studied revealing the same molecular mechanisms in play as found in the cancer cell culture and animal studies, namely, cancer cells were induced to undergo Programmed Cell Death with evidence of both autophagy and apoptosis.(3) Left Image : typical enhancing Glioblastoma on MRI Brain srudy, courtesy wikimedia commons.

Overly Heroic ?

In my opinion, direct infusion of THC into the brain is overly heroic and completely unnecessary, as excellent results for malignant brain tumors are currently obtained with oral administration of cannabis oil.  The use of cannabis oil was pioneered by Rick Simpson, a Canadian who uploaded a You-Tube video called Run From the Cure which popularized a “Do-It-Your-Self-at-Home” method of making Cannabis Oil for personal medical use.

Mara Gordon of Aunt Zeldas

A more sophisticated approach utilizes Steep Hill Halent lab testing of various cannabis strains to find a combination of two strains providing both THC and CBD in high yield. Mara Gordon of Aunt Zelda’s in California reports good results by combining two cannabis strains, one high in THC and the other high in CBD.   Her report describes excellent results with this regimen for pediatric cancer patients, some of which were malignant brain tumors.

The Vacuum Phenomenon- A Dearth of Clinical Studies

As this Pilot Study by Guzman is the only human study of cannabis in Glioblastoma, the complete absence of additional clinical studies is astounding.  However, when one realizes cannabis is a natural plant substance which, by definition,  cannot be patented and therefore of no interest to the pharmaceutical industry, this becomes more understandable.  In addition, like any other natural substance, large scale clinical trials using Cannabis Oil as a cancer treatment are unlikely to ever take place.   Instead I expect future randomized clinical trials by drug companies seeking FDA approval on patented molecules or materials derived from the cannabis plant.  Examples are drugs such as dronabinol, nabiximols and nabilone.

A Government Paradox

In spite of the obvious rule that natural substances cannot be patented, the US government has a patent on medicinal use of  “Cannabinoids as  antioxidants and neuroprotectants”  (US 6630507 B1).  It would appear paradoxical that a US government agency Dept of Health and Human Services(HHS), would hold such as patent, and at the same time another US government agency, the DEA, declare a ruling that Cannabis “has no accepted medical use”.  Perhaps the DEA should talk to HHS.  People heavily involved in working to promote medicinal cannabis legislation might be enraged by this.  However, most other people would simply throw up their hands, shrug their shoulders and say,”Well, that’s the government for you“.  Upper left image courtesy of Ronald Reagan Quotes

As of June 2014 , 23 states have legalized the use of medicinal cannabis.

More Patents

In Dec 2013, GW Pharmaceuticals announced its patent for use of the Cannabinoids, THC and CBD in a 1:1 ratio, for treating Gliomas.  Sativex(R) is their plant-derived cannabinoid prescription drug which has a 1:1 ratio of THC to CBD.  A clinical trial of Sativex in recurrent glioblastoma patients is currently underway, and not yet completed.

Paola Massi, PhD is a prolific cannabis researcher at University of Milan in the Department of Cellular and Molecular Pharmacology. Left Image: University of Milan Courtesy of Wikimedia commons.

I recommend to you her 2013 report in the British Journal of Medical Pharmacology entitled, “Medical cannabidiol – is there anything it can’t do?” (8) In this report, Dr Massi says:

” cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization.”(8)

Dr. Massi’s medical literature review on the anticancer activity of cannabinoids again supports the “Whack-A-Mole” concept of cancer inhibition, with differing pathways and mechanisms found depending on the cancer model studied.(8)   Dr. Massi’s  review covers  5 different cancer types, Breast cancer, Glioma,Leukemia, thyroid cancer, colon cancer noting the type of cannabinoid receptor involvement, production of ROS (reactive oxygen), molecular cell signalling,  and presence or absence of autophagy and apoptosis, (See Table 1 for this information) (8).

Basic Science Methods

The basic science of cannabis cancer research  involves studying cancer cells in cultures by treating them with cannabinoids (mainly THC and CBD) and other agents, after which the cancer cells are studied to determine the effect.  A second method is the in-vivo animal study usually done with mice injected with cancer cells (called a xenograft),  and then treated with cannabis agents.  The mice are observed, later sacrificed and organs studied to determine effect.(8)

Breast Cancer

Vincent DiMarzo’s Group in Italy studied breast cancer in a xenograft animal model. They used subcutaneous injection human breast cancer cells (MDA-MB-231 cells) into mice.  Their 2006 paper showed Cannabidiol (CBD) to be the most potent inhibitor of cancer cell growth, with cancer cells undergoing apoptosis.  Lung metastases were reduced and inhibited in the mice, as well.(16)  Left image courtesy of Vincent DiMarzo.

McAllister’s Group continued this line of study, publishing in 2011 Breast Cancer Research their paper further delineating the pathways by which Cannabidiol reduces breast cancer cell growth, invasion and spread (metastases).  They found that CBD works through the ERK/MAPK pathway, and the ROS(Reactive Oxygen Species) pathways, both leading to down-regulation of Id-1 gene, a key gene in cancer biology.

Shrivastava et al. studied the effect of CBD on human breast cell lines and their 2011 paper reported induction of cancer cell death by apoptosis and autophagy.  Further studies of the molecular pathways involved, showed  ER (endoplasmic reticulum stress) and production of ROS (reactive oxygen species).  They found that CBD reduced mitochondrial membrane potential (opened VDAC channels) which released Cytochrome C into the cytosol, and activated programmed cell death through the intrinsic pathway.  Going further, with even more elegant studies, Shrivastavs’s group blocked the apoptotic cell death pathway by adding Caspase inhibitors to the CBD treated cancer cells, after which she found compensatory increase in the autophagy pathway of cell death.  This supports the “Whack-a-Mole” concept in which blocking one pathway to cell death merely leads to preferential use of an alternate pathway.

Gliomas

Gliomas are cancers which originates in brain tissue, also called glioblastoma, astrocytoma, etc.  Gliomas are perhaps the most devastating, tending to be very aggressive with high recurrence rate after chemotherapy and radiation therapy,

Prognosis for this type of cancer is unusually poor even among privileged sectors of our society who can afford “the best” health care.  Senator Senator Edward Kennedy, who had access to the most prestigious medical facilities,  succumbed to Glioblastoma 15 months after diagnosis,  a mere three months longer than the 12.1 month median survival time for the disease.  In 2005, a new drug, temozolomide increased median survival time from 12.2 months to  14.6 months, admittedly a small improvement, but not much to brag about.  Left Image: Sen Ed Kennedy courtesy of NY Daily News.

Early work from Sweden by Jacobssen published in 2000 showed both THC and CBD inhibited glioma cells in culture with “modest reduction in cell viability”.

A 2004 report by Paola Massi studied the effect of CBD on U87 and U373 human glioma cell lines which appeared to be CB2 receptor dependent and secondary to ROS (reactive oxygen species) generation.  When the CBD was added to the brain cancer cells, there was  a dramatic reduction in mitochondrial oxidative metabolism, resulting in an anti-proliferative effect and induction of apoptosis, which was partially blocked by addition of a CB2 receptor antagonist, and by anti-oxidant Vitamin E (alpha- tocopherol).  In a subsequent xenograft animal model, CBD injected into mice significantly inhibited the growth of implanted human brain cancer cells.

Further studies were done by Massi pubished in a 2006 report, further elucidating the molecular pathways leading to apoptosis by CBD in her human glioma cell model.  She demonstrated that Mitochondrial release of cytochrome C, Caspase activation and reactive oxygen species (ROS) induction triggered the apoptosis in the CBD treated human glioma cells.  CBD treated normal glioma cells were left unharmed, again showing selectivity.

Further studies published in a  2013 report by Dr. Massi again using CBD treated human glioma cancer cells (U87-MG and T98G cells) showed decreased cell proliferation and invasiveness in the CBD treated cancer cells.  Examining protein expression, Dr Massi found the cancer cells pretreated with CBD showed reduction in production of proteins involved in growth, invasion and angiogenesis of the cancer cells.   Signalling pathways were studied showing CBD induced down-regulation of ERK, and Akt signaling pathways in glioma cells.  There was also decreased hypoxia inducible factor HIF-1α in CBD treated cancer cells.  Dr. Massi showed CBD anti-cancer activity utilized multiple pathways, again supporting the “Whack-A-Mole” concept.  When one pathway is blocked or absent, another one is used to accomplished PCD, programmed cell death.

Other natural plant substances that inhibit glioma cells: Marchantin C, isolated from the Liverwort plant, was found to produce apoptosis in glioma cells in this 2009 report.

Berberine

Others: Berberine and Plumbagin are additional natural plant substances that induce apoptosis in cancer cells.  More studies on Berberine inducing apoptosis in cancer cells can be found here.  Similar to the Cannibinoids, Berberine induces apoptosis in cancer cells through the Mitochondrial/Caspase dependent pathway.

Artemesinin ( Chinese Wormwood)

An anti-malarial Chinese herb, artemesia, has been found to have profound anti-cancer activity against multiple cancer cell lines. Studies show induction of apoptosis through mitochondrial pathways. Approximately 400 studies have been published in the scientific literature in recent years.
Click on this link: Artemisinin_anti-Cancer_Publications, for the list of publications. Click on this link for an excellent review:
Artemisinins_Krishna_Trends_Pharmacological_Science_2008

Reveratrol, Pterostilebene and methyl jasmonate

Reservatrol and its derivative Pterostilbene,from grapes and berries,  show strong anticancer activity via induction of apoptosis in cancer cell lines.  See my previous article on Pterostilbene.  Methyl jasmonate is another plant compound ubiquitous in the plant kingdom which acts directly on the mitochondria to induce apoptosisin cancer cell lines.  Methyl Jasmonate was found to work synergistically with other anti-cancer agents such as common chemotherapeutic drugs and glycolysis inhibitors.

Leukemia

Early studies in 2003 by Gallily at Hebrew University in Jerusalem showed cannabidiol (CBD) induced apoptosis via caspase activation in human leukemia cell culture (HL-60 cells).  Giving the leukemia cells a short burst of radiation therapy prior to CBD enhanced the effect, attaining a 90-85% cell death rate.  Normal white cells were left unharmed.

Continuing Paola Massi’s earlier work, Dr.McKallip’s group published in 2006 their studies of the effect of CBD (cannabidiol) on leukemia cells , again finding CBD induces apoptosis with increased ROS (reactive oxygen species), acting through the CB2 receptor.   This is indeed fortuitous, because leukemia and lymphoma cell lines are known to over-express CB2 receptors.  (ie Leukemic cells have a higher number of CB2 receptors, and thus are more sensitive to the CB2 mediated effects of CBD.)

Another Patent

Dr. Robert McKallip et al.published a patent in 2004 on the medicinal use of CBD in lymphoma and leukemia.

Lung Cancer

Ramer’s group at the Unviersity of Rostock in Germany has done excellent work on CBD use in lung cancer with a 2012 report published in FASEB.  They found early-onset upregulation (four-fold) of ICAM-1  (intercellular adhesion molecule-1) via cannabinoid receptors in CDB treated lung cancer cells.  Later, 48 hrs on, they found upregulation of the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) accounting for the loss of invasiveness of the lung cancer cells.  In-vivo experiments injecting lung cancer cells (A549, H358, and H460) into mice then treated with CBD showed 2-3 fold increase in ICAM-1 and TIMP-1 protein which decreased cancer cell invasiveness.  Upon microscopic inspection, the number of lung metastatic lesions had been reduced in half in the CBD treated mice.  In yet another study, Ramers group also discovered a new mechanism, the downregulation of the plasminogen activator inhibitor PAI-1, a protein involved in tumor invasiveness.

CBD Concentrations Similar to Human Use of Sativex

The CBD concentrations used in the Dr Ramer’s animal studies which decreased invasiveness of lung cancer in-vivo  were similar to the reported plasma concentrations of CBD ( 2.0-5.0 ng/ml) in healthy volunteers following administration of Sativex^TM. , the oral mucosal spray product by GW pharmaceuticals which has a 1:1 ratoi of CBD to THC..(reference see the Sativex_Product_Monograph_GW_Pharma_CBD_THC)

Dr Massi concludes her 2013 paper by stating:

“Collectively, the non-psychoactive plant-derived cannabinoid CBD exhibits pro-apoptotic and anti-proliferative actions in different types of tumours and may also exert anti-migratory, anti-invasive, anti-metastatic and perhaps anti-angiogenic properties. On the basis of these results, evidence is emerging to suggest that CBD is a potent inhibitor of both cancer growth and spread…..the anticancer effect of this compound seems to be selective for cancer cells, at least in vitro, since it does not affect normal cell lines. The efficacy of CBD is linked to its ability to target multiple cellular pathways that control tumourigenesis through the modulation of different intracellular signalling depending on the cancer type considered.” Massi BJCP 2013.

What is Evidence ?

A word of caution is in order here as to what exacty constitutes evidence. .  Although, as you can see,  we we have presented many basic science studies on the anti-cancer activity of cannabinoids THC and CBD, mainstream medical doctors will say with a wave of the hand, “none of this is evidence”.   There are many anectodal case histories of remission from cancer with the use of medicinal cannabis.  Again, mainstream medical doctors will reject this with a wave of the hand, saying, “none of this is evidence”.

For mainstream medicine which is dominated by the drug industry, the only real evidence is the double blind placebo controlled drug trial, typically required for FDA drug approval. As we mentioned above, we don’t have any of these and I don’t expect we ever will for the cannabis plant, or for any plant or natural substance for that matter.  The reason for this is that the cannabis plant is a  natural substance which cannot be patented, and therefore of little interest to the drug companies who would never imaging spending the millions of dollars on expensive drug studies.

The RCT

We must remember that the randomized controlled trial (RCT) is a type of drug study required for FDA approval of a drug.  It is not intended nor is it usually used to initiate a treatment modality.  Treatment is usually based on the good doctor’s clinical judgement, which may be based on observational studies, case reports, personal experience, and all other forms of medical evidence described above.

A Vending Machine For the Pharmaceutical Industry

So we are still faced with this criticism from mainstream medicine that our natural substance, the cannabis plant, has no randomized controlled trials.  My answer to this is the following:  It is an error to believe that the only  form of “medical evidence” consists of a double blind placebo controlled drug trial, and all else is “not evidence”     Sadly, the art of clinical observation in the practice of medicine has been lost, and Institutional Medicine has transformed into a  “vending machine” for the pharmaceutical industry.  In order to be a good vending machine, we must give ourselves temporary amnesia, and when convenient, forget about all other forms of medical evidence.

Medical Evidence- Challenge-Rechallenge Proof of Causality

Regarding the anecdotal case reports of medical cannabis non-nonchalantly dismissed by our mainstream medicine colleagues, these anecdotal case reports which include Challenge-Rechallenge-Dechallenge (CRD) are held as the highest level of evidence, and considered proof of causality by our Court System, the FDA and the World Health Organization.

How to Ban a Drug

Let’s say hypothetically a questionable drug is suspected of producing horrendous adverse side effects which, if true, would serve as grounds to ban the drug. The  CRD argument is accepted by the court system and the FDA, and is commonly relied upon to prove yes these adverse side effects are indeed caused by the drug in question, and  the drug is then banned from the marketplace.

References for Challenge Rechallenge

Evidence_Medical_Legal_Donald_Miller_2005

Causality Assessment of Suspected Adverse Drug6_pdf

Evidence_Medical_Legal_Donald_W_Miller_2006

Limitations fo the Randomized Controlled Trial

The Randomized Controlled Trial was designed to protect the public from “bad drugs”.  However, of all the drugs granted FDA approval based on RCT studies, demonstrating the drug to be more effective compared to placebo,  Ten Per Cent are later banned, and another Ten Per Cent are given a “Black Box” Warning.  Obviously, there are problems with these Randomized Controlled Trials. The drug companies have corrupted the drug trial system to rig the results in their favor. How do they do it?  They use various well known gimmicks such as data manipulation, restricting the entry criteria, Medical Ghost-Writing, with-holding negative results from publication, etc.

An example: The SSRI antidepressant drugs were granted FDA approval based on manipulated studies.  Years later, the truth was revealed in a JAMA report.  The SSRI drug magnitude of benefit compared to placebo is “minimal or nonexistent” for mild to moderate depression.

Another example: A Double Blind Placebo controlled study was conducted and FDA approval granted in June 2013 for the drug paroxetine, an SSRi antidepressant, as treatment for menopausal symptoms of “hot flashes”.  Efficacy over placebo was marginal.   In my opinion, the use of psycho-active drugs such as SSRI anti-depressants for treatment of symptoms caused by menopausal  hormone deficiency is an abuse and mistreatment of women belonging in a medical museum as an example of medical iatrogenesis.  Not only is paroxetine, medically ineffective for treatment of menopausal symptoms (a hormone deficiency state),  paroxetine is one of the most addictive of the SSRI drugs,  and the FDA has warned that withdrawal from paroxetine can be severe. (BMJ).  The drug has numerous adverse side effects including increased suicidal activity , loss of libido and sexual dysfunction.  The medical practice of prescribing  SSRI antidepressant and other psychiatric drugs for treatment of menopausal symptoms in women borders on criminal behavior by the medical system.  This is a medical practice that should be halted immediately.

This is only one example of criminal mischief by the drug industry.  More misconduct can be found permeating the medical literature.  Examples include statin anti-cholesterol drugs, bisphosphonate osteoporosis drugs, synthetic hormone drugs,  and of course, the granddaddy of all, the anti-psychotic drugs, all carefully documented in a number of books on this topic such as Dr Marcia Angell’s book, The Truth About the Drug Companies: How They Deceive Us
and Dr Peter Goetsche’s book, Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare.

Convenient Episodes of Temporary Amnesia

Here is another example of “temporary amnesia” by our medical colleagues who insist on “evidence” of the randomized drug trial.  The popular thyroid medicine,  levothyroxine, Synthroid(r),  was “Grandfathered In ” and prescribed by practitioners for 46 years without any randomized trials or formal FDA approval.  This was rectified in  July, 2002 when Synthroid(r) finally received FDA approval.  How could doctors prescribe a drug for 46 years without “evidence” ?  Solution: Just give yourself temporary amnesia.

Prescribing Natural Substances At the Hospital

The Mainstream Medical Doctor who dismisses natural substances claiming there is “no evidence”  must self administer a convenient lapse in memory when they prescribe one of many natural substances listed in the Hospital Formulary.  Like the above synthroid (r) example, these have been “GrandFathered In”.

Examples: Parenteral Vitamin C, IV Isotonic Saline, Red Blood cell transfusions,  Parenteral thiamine, parenteral B12, IV Magnesium, IV oxytocxin (Pit-Drip) used in obstetrics.  There are many more. These are all natural substances which cannot be patented, and therefore no randomized trial will ever be forthcoming.

The Off Label Use of FDA approved Drugs

Again, temporary amnesia is required by our mainstream medicine colleagues for the common practice of prescribing drugs Off-Label.  This is the use of a drug for medical indications other than the orginal FDA approved indication.  These are drugs anecdotally effective, however, they are off-patent with no randomized controlled trials completed or even to be expected for the off-label use.

An example of this is Clomiphene, FDA approved to induce ovulation in women to increase fertility.  Off-label use of clomiphene in young males  to increase testosterone levels while preserving fertility is quite effective in observational studies, and verified in my office with challenge-dechallenge-rechallenge type protocols.

Surgical Procedures

When dismissing natural substances, the mainstream practitioner will conveniently suffer from temporary amnesia regarding another point: Many surgical procedures have never been submitted to the rigors of a randomized trial, and when they are, they are sometimes found to be sham procedures.  Arthroscopic knee surgery for osteoarthritis and bone marrow transplant for breast cancer were performed for years until the truth was finally revealed.  They were no better than placebo.

Why Most Published Research Finding Are False

According to Dr. John P.A. Ioannidis, who published his 2005 article entitled, “ Why Most Published Research Findings Are False“, as much as 90% of the published information in medical journals doctors rely on is flawed.  In order to carry on, and survive their day at the clinic or hospital, mainstream medical doctors must again self administer temporary amnesia.  They must  ignore or forget this unpleasant nonsense about how the published medical information they rely on is biased, unreliable, flawed and downright wrong.

Observational Studies Are Evidence

More examples in which treatment is based on clinical observation studies, and not on randomized controlled trials:

Wernicke’s encephalopathy in infants was reported in Israel caused by thiamine deficient feeding formula.  The authors state: “Clinician awareness of the possibility of thiamine deficiency … is important for …prevention of irreversible brain damage. Therapy with large doses of thiamine should be initiated at the earliest suspicion of vitamin depletion, even before laboratory evidence is available.”    Thiamin is a natural substance in the body, a vitamin, so there are no randomized controlled trials.  This medical practice is based on observational studies.

Folate supplementation is given to child bearing women to prevent neural tube defects.  Folate is a natural substance in the body, a vitamin, so there are no RCTs.  This medical practice is based on observational studies.

Sudden onset of psychosis and other neurological disease is a treatable cause of B12 deficiency.  B12 is a natural substance in the body, a vitamin, so there are no RCTS for B12, and this medical practice is based on observational studies.

Intravenous Vitamin C and other anti-oxidants are given to critically ill patients in the Intensive Care Unit.  Vitamin C is a natural substance, a vitamin, so there are no drug company randomized trials.   (Vitamin C Saves Life of Dying Man)

Likewise for phyto-cannabinoids which mimic endogenous cannabinoids in the body, similar to the above examples, these are natural substances which cannot be patented and unlikely to ever undergo randomized drug trials.

If you look at the enormous body of scientific knowledge we have with basic science, laboratory and animal studies, observational studies, anecdotal case histories, personal accounts published on the internet, etc, I say this is all “evidence” which massively overshadows and dwarfs the relatively miniscule world of the patented drug study. The volume of publications for patented drugs is only a small fraction of the entire body of medical science knowledge we have accumulated.  To reject this larger body of scientific knowledge as “not evidence” is merely a ruse, a form of self-censorship motivated by politics.  It’s high time we exposed this as a ruse, no pun intended.

Articles with Related Interest:

How Does Cannabis Kill Cancer Cells Part One

Pediatric Cancer and Cannabis Oil

Cannabis Oil for Acute Leukemia

Medical Cannabis for Epilepsy PArt Two

Medical Cannabis for Epilepsy Part One

Cannabis Oil Brain Tumor remission

Remission from Astrocytoma

Medical Marijuana Research Supressed

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
http://www.jeffreydachmd.com
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http://www.bioidenticalhormones101.com

Link to this article: http://wp.me/p3gFbV-24A

References:

Dr Manuel Guzmán

1) cannabinoids_as_antitumour_agents_Manuel_Guzman_2012
Velasco, Guillermo, Cristina Sánchez, and Manuel Guzmán. “Towards the use of cannabinoids as antitumour agents.” Nature Reviews Cancer 12.6 (2012): 436-444.

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2002

2) http://www.ncbi.nlm.nih.gov/pubmed/12435806  full text free
Mol Pharmacol. 2002 Dec;62(6):1385-92.
Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor. Galve-Roperh I1, Rueda D, Gómez del Pulgar T, Velasco G, Guzmán M.

Cannabinoids, the active components of marijuana and their endogenous counterparts, exert many of their actions in brain through the seven-transmembrane receptor CB(1).

This receptor is coupled to the activation of the extracellular signal-regulated kinase (ERK) cascade. However, the precise molecular mechanism for CB(1)-mediated ERK activation is still unknown. Here, we show that in U373 MG human astrocytoma cells, CB(1) receptor activation with the cannabinoid agonist delta(8)-tetrahydrocannabinol dimethyl heptyl (HU-210) was coupled to ERK activation and protection from ceramide-induced apoptosis. HU-210-induced ERK activation was inhibited by tyrphostin AG1478 and PP2, widely employed inhibitors of the epidermal growth factor receptor (EGF(R)) and the Src family of cytosolic tyrosine kinases, respectively. However, HU-210 stimulation resulted in neither EGF(R) phosphorylation, Src tyrosine phosphorylation, nor increased Src activity. In addition, dominant-negative forms of both proteins were unable to prevent cannabinoid-induced ERK activation, thus excluding the existence of CB(1)-mediated EGF(R) transactivation or Src activation. Wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294,002), inhibitors of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, blocked cannabinoid-induced ERK activation. Likewise, HU-210 stimulated the PI3K downstream targets protein kinase B (PKB), as shown by its phosphorylation in Thr 308 and Ser 473 residues, and Raf-1. Moreover, betagamma subunit release mimicked ERK and PI3K/PKB activation, suggesting that activation of class IB PI3K mediates cannabinoid action. Pro-survival HU-210 action also required activation of both PI3K and ERK signaling pathways. In conclusion, CB(1)-induced ERK activation was mediated by PI3K(IB) and this effect may have important consequences in the control of cell death/survival decision.

2006 – Glioblastoma Pilot Study

3) http://www.nature.com/bjc/journal/v95/n2/full/6603236a.html
Guzman M, Duarte MJ, Blazquez C, Ravina J, Rosa MC, et al. (2006) A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95: 197–203.  British Journal of Cancer (2006) 95, 197–203. Published online 27 June 2006

A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme M Guzmán1, M J Duarte2, C Blázquez1, J Ravina2, M C Rosa2, I Galve-Roperh1, C Sánchez1, G Velasco1 and L González-Feria2
1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid 28040, Spain
2Department of Neurosurgery, Hospital Universitario de Canarias, La Laguna, Tenerife 38320, Spain

D9-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15–33). D9-Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

2005  Ceramide Signalling

4) http://www.ncbi.nlm.nih.gov/pubmed/15958274
Life Sci. 2005 Aug 19;77(14):1723-31.
Cannabinoids and ceramide: two lipids acting hand-by-hand.
Velasco G1, Galve-Roperh I, Sánchez C, Blázquez C, Haro A, Guzmán M.
1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.

Cannabinoids, the active components of Cannabis sativa (marijuana) and their endogenous counterparts, exert their effects by binding to specific G-protein-coupled receptors that modulate adenylyl cyclase and ion channels. Recent research has shown that the CB1 cannabinoid receptor is also coupled to the generation of the lipid second messenger ceramide via two different pathways: sphingomyelin hydrolysis and ceramide synthesis de novo. Sustained ceramide accumulation in tumor cells mediates cannabinoid-induced apoptosis, as evidenced by in vitro and in vivo studies. This effect seems to be due to the impact of ceramide on key cell signalling systems such as the extracellular signal-regulated kinase cascade and the Akt pathway. These findings provide a new conceptual view on how cannabinoids act, and raise interesting physiological and therapeutic questions.

2006 Manual guzman Pancreatic CA

5) http://cancerres.aacrjournals.org/content/66/13/6748.full.html

Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum Stress–Related Genes  Cancer Res. 2006 Jul 1;66(13):6748-55.

Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease. The present study was undertaken to investigate the action of cannabinoids, a new family of potential antitumoral agents, in pancreatic cancer. We show that cannabinoid receptors are expressed in human pancreatic tumor cell lines and tumor biopsies at much higher levels than in normal pancreatic tissue. Studies conducted with MiaPaCa2 and Panc1 cell lines showed that cannabinoid administration (a) induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. These effects were prevented by blockade of the CB(2) cannabinoid receptor or by pharmacologic inhibition of ceramide synthesis de novo. Knockdown experiments using selective small interfering RNAs showed the involvement of p8 via its downstream endoplasmic reticulum stress-related targets activating transcription factor 4 (ATF-4) and TRB3 in Delta(9)-tetrahydrocannabinol-induced apoptosis. Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue. In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB(2) receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress-related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer.

Pancreatic cancer is one of the most malignant and aggressive forms of cancer ( 1). With an incidence of 10/10,000 for men and 7/10,000 for women, it represents the fourth most common death-causing cancer in the United States ( 2) and the fifth in the Western world overall ( 3). About 95% of pancreatic cancers cases are ductal adenocarcinomas. The anatomic localization of the pancreas and the nonspecific nature of the symptoms result in a complex and delayed diagnosis. Therefore, at the time of detection, 85% of patients show metastasic infiltrations in proximal lymphatic nodes, liver, or lungs, and only 15% to 20% of the tumors are typically found resectable ( 1). In addition, <20% of the operated patients survive up to 5 years. Treatment of unresectable tumors is currently based on administration of fluorouracil chemoradiation for locally advanced tumors and gemcitabine chemotherapy for metastatic disease ( 1). However, despite maximal optimization of these therapies, the median survival for the affected patients remains ∼1 year. This antitumoral action of cannabinoids relies, at least in part, on the ability of these compounds to directly affect the viability, via induction of apoptosis or cell cycle arrest, of a wide spectrum of tumor cells in culture

THC induces apoptosis of pancreatic tumor cells.

In the present report, we show that cannabinoids induce apoptosis of pancreatic tumor cell lines in vitro and exert a remarkable growth-inhibiting effect in models of pancreatic cancer in vivo.

Of potential interest for future cannabinoid-based therapies, cannabinoid treatment does not seem to activate this pathway in normal pancreas or spleen, suggesting that these agents may activate the endoplasmic reticulum stress proapoptotic pathway selectively in tumor cells.

Thus, our findings indicate that the mechanism of cannabinoid-induced apoptosis of human pancreatic tumor cells involves a CB2 receptor–dependent accumulation of de novo synthesized ceramide that leads to p8, ATF-4, and TRB3 up-regulation

6) http://www.ncbi.nlm.nih.gov/pubmed/24309936   full
Cell Death Dis. 2013 Dec 5;4:e949.

Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death.  Rimmerman N1, Ben-Hail D, Porat Z, Juknat A, Kozela E, Daniels MP, Connelly PS, Leishman E, Bradshaw HB, Shoshan-Barmatz V, Vogel Z.The Dr. Miriam and Sheldon G Adelson Center for the Biology of Addictive Diseases, Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

7) 2012 full pdf

cannabinoids_as_antitumour_agents_Manuel_Guzman_2012

Towards the use of cannabinoids as antitumour agents Guillermo Velasco, Cristina Sánchez and Manuel Guzmán  Nature Reviews Cancer 12.6 (2012): 436-444.

Abstract | Various reports have shown that cannabinoids (the active components
of marijuana and their derivatives) can reduce tumour growth and progression in
animal models of cancer, in addition to their well-known palliative effects on some
cancer-associated symptoms. This Opinion article discusses our current
understanding of cannabinoids as antitumour agents, focusing on recent insights
into the molecular mechanisms of action, including emerging resistance
mechanisms and opportunities for combination therapy approaches. Such
knowledge is required for the optimization of preclinical cannabinoid-based
therapies and for the preliminary clinical testing that is currently underway.

Sanchez C, Galve-Roperh I, Canova C, Brachet P, Guzman M (1998)
Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett 436: 6–10.

Galve-Roperh I, Rueda D, Gomez del Pulgar T, Velasco G, Guzman M (2002)
Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor. Mol Pharmacol 62: 1385–1392.

Galve-Roperh I, Aguado T, Palazuelos J, Guzman M (2008)
Mechanisms of control of neuron survival by the endocannabinoid system. Curr Pharm Des 14: 2279–2288.

undated

http://cannabis-med.org/index.php?tpl=faq&red=faqlist&id=274&lng=en
Cancer: Do cannabinoids cure cancer?  by Dr Manuel Guzmán
Dr Manuel Guzman is professor at the Department of Biochemistry and Molecular Biology at Complutense University in Madrid, Spain. He coordinates the Cannabinoid Signaling Group.

____________________________________

2013 Paola Massi PhD Dept. of Pharmacology, Chemotherapy and Toxicology of the University of Milan as Assistant Professor in Cellular and Molecular Pharmacology.

8) http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2012.04298.x/full
Medical cannabidiol – is there anything it can’t do?

Cannabidiol as potential anticancer drug  British Journal of Clinical Pharmacology
Volume 75, Issue 2, pages 303–312, February 2013     Paola Massi 1,    Marta Solinas2,    Valentina Cinquina2 and      Daniela Parolaro2,*

2013

9) http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0076918

Cannabidiol, a Non-Psychoactive Cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect by Marta Solinas,    Paola Massi,    Valentina Cinquina,     Marta Valenti,     Daniele Bolognini,     Marzia Gariboldi,     Elena Monti,     Tiziana Rubino,     Daniela Parolaro mail Published: October 21, 2013 in PLoS ONE 8(10): e76918

2010

10) http://www.mdpi.com/2072-6694/2/2/1013/htm
Cancers 2010, 2(2), 1013-1026;
Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress by Paola Massi 1, Marta Valenti 2, Marta Solinas 2 and Daniela Parolaro 2,* 1 Department of Pharmacology, Chemotherapy and Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy;

 

==============================

2013  Italy University of Salerno, Salerno, Italy; Endocannabinoid Research Group, Department of Medicine and Surgery, University of Salerno, Salerno, Italy. Electronic address: .

full pdf  2013
Endocannabinoid_system_modulation_in_cancer biology and therapy_pisanti_bifulco_2009

11) The endocannabinoid signaling system in cancer
Trends in Pharmacological Sciences (Impact Factor: 9.25). 04/2013;
Simona Pisanti1,2, Paola Picardi1,2, Alba D’Alessandro1,2, Chiara Laezza3, and  Maurizio Bifulco1,2 .  Endocannabinoid Research Group, Department of Pharmacy, University of Salerno, Salerno, Italy; Endocannabinoid Research Group, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.

 

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770515/     free full

12) Cancer Manag Res. 2013 Aug 30;5:301-13.  Critical appraisal of the potential use of cannabinoids in cancer management. Cridge BJ1, Rosengren RJ.    1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
Cannabinoids have been attracting a great deal of interest as potential anticancer agents. Originally derived from the plant Cannabis sativa, there are now a number of endo-, phyto- and synthetic cannabinoids available. This review summarizes the key literature to date around the actions, antitumor activity, and mechanisms of action for this broad range of compounds. Cannabinoids are largely defined by an ability to activate the cannabinoid receptors – CB1 or CB2. The action of the cannabinoids is very dependent on the exact ligand tested, the dose, and the duration of exposure. Some cannabinoids, synthetic or plant-derived, show potential as therapeutic agents, and evidence across a range of cancers and evidence in vitro and in vivo is starting to be accumulated. Studies have now been conducted in a wide range of cell lines, including glioma, breast, prostate, endothelial, liver, and lung. This work is complemented by an increasing body of evidence from in vivo models. However, many of these results remain contradictory, an issue that is not currently able to be resolved through current knowledge of mechanisms of action. While there is a developing understanding of potential mechanisms of action, with the extracellular signal-regulated kinase pathway emerging as a critical signaling juncture in combination with an important role for ceramide and lipid signaling, the relative importance of each pathway is yet to be determined. The interplay between the intracellular pathways of autophagy versus apoptosis is a recent development that is discussed. Overall, there is still a great deal of conflicting evidence around the future utility of the cannabinoids, natural or synthetic, as therapeutic agents.

Endogenous cannabinoids regulate the de novo synthesis of ceramides, lipid-based components of the cell membrane that perform both structural and signaling functions. It is becoming increasingly obvious that ceramide functions as a physiological signaling molecule, particularly with regard to the control of apoptosis, but also growth arrest, differentiation, cell migration, and adhesion.104 As such, the role and regulation of ceramide signaling is attracting increasing attention, and ceramide now has an accepted role in the development of some cancers.105 Activation of either CB1 or CB2 in glioma cells is associated with an increase in ceramide levels leading to the activation of the extracellular signal
regulated kinase (ERK) pathway via Raf-1 activation and p38 MAPK activation.14,106 Both these pathways ultimately cause apoptosis through caspase activation and/or cell-cycle arrest.14 In breast cancer cells, the CB1 antagonist SR141716 inhibited cell proliferation through the effects of ERK1/2 colocalized inside membrane lipid rafts/caveloae.59 Such rafts play a critical role in the growth and metastasis of breast tumors.107,108 A final component of the ERK pathway, p53, plays a crucial role in switching between cell-cycle arrest and apoptosis.109 In cultured cortical neurons, ?9-THC activated p53 via the CB1 receptor, thereby activating the apoptotic cascade involving B-cell lymphoma (Bcl)-2 and Bcl-2-

It is a distinct possibility that the cannabinoids may have a place in the future treatment of cancer.

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Apoptosis

13) http://europepmc.org/articles/PMC2117903
Toxicol Pathol. 2007; 35(4): 495–516.
Apoptosis: A Review of Programmed Cell Death  Susan Elmore
The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

14) http://www.ncbi.nlm.nih.gov/pubmed/4561027
Kerr JF, Wyllie AH, Currie AR (August 1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26 (4): 239–57. Br J Cancer. 1972 Aug;26(4):239-57.

The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological.The structural changes take place in two discrete stages. The first comprises nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments. In the second stage these apoptotic bodies are shed from epithelial-lined surfaces or are taken up by other cells, where they undergo a series of changes resembling in vitro autolysis within phagosomes, and are rapidly degraded by lysosomal enzymes derived from the ingesting cells.Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development. It occurs spontaneously in untreated malignant neoplasms, and participates in at least some types of therapeutically induced tumour regression. It is implicated in both physiological involution and atrophy of various tissues and organs. It can also be triggered by noxious agents, both in the embryo and adult animal.

15) http://www.ncbi.nlm.nih.gov/books/NBK26873/
Cell Biology 4th Edition Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002

Cells that die as a result of acute injury typically swell and burst. They spill their contents all over their neighbors—a process called cell necrosis—causing a potentially damaging inflammatory response. By contrast, a cell that undergoes apoptosis dies neatly, without damaging its neighbors. The cell shrinks and condenses. The cytoskeleton collapses, the nuclear envelope disassembles, and the nuclear DNA breaks up into fragments. Most importantly, the cell surface is altered, displaying properties that cause the dying cell to be rapidly phagocytosed, either by a neighboring cell or by a macrophage (a specialized phagocytic cell, discussed in Chapter 24), before any leakage of its contents occurs (Figure 17-37). This not only avoids the damaging consequences of cell necrosis but also allows the organic components of the dead cell to be recycled by the cell that ingests it.

16) Breast Cancer 2006 Di Marzo

16) http://www.ncbi.nlm.nih.gov/pubmed/16728591
J Pharmacol Exp Ther. 2006 Sep;318(3):1375-87. Epub 2006 May 25.
Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma.
Ligresti A1, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V.
1Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche Pozzuoli, Italy.
Delta(9)-Tetrahydrocannabinol (THC) exhibits antitumor effects on various cancer cell types, but its use in chemotherapy is limited by its psychotropic activity. We investigated the antitumor activities of other plant cannabinoids, i.e., cannabidiol, cannabigerol, cannabichromene, cannabidiol acid and THC acid, and assessed whether there is any advantage in using Cannabis extracts (enriched in either cannabidiol or THC) over pure cannabinoids. Results obtained in a panel of tumor cell lines clearly indicate that, of the five natural compounds tested, cannabidiol is the most potent inhibitor of cancer cell growth (IC(50) between 6.0 and 10.6 microM), with significantly lower potency in noncancer cells. The cannabidiol-rich extract was equipotent to cannabidiol, whereas cannabigerol and cannabichromene followed in the rank of potency. Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by s.c. injection into athymic mice of human MDA-MB-231 breast carcinoma or rat v-K-ras-transformed thyroid epithelial cells and reduced lung metastases deriving from intrapaw injection of MDA-MB-231 cells. Judging from several experiments on its possible cellular and molecular mechanisms of action, we propose that cannabidiol lacks a unique mode of action in the cell lines investigated. At least for MDA-MB-231 cells, however, our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: direct or indirect activation of cannabinoid CB(2) and vanilloid transient receptor potential vanilloid type-1 receptors and cannabinoid/vanilloid receptor-independent elevation of intracellular Ca(2+) and reactive oxygen species. Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.

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Ceramide

Free full text  ceramide

http://cancerres.aacrjournals.org/content/61/3/1233.long
Cancer Res. 2001 Feb 1;61(3):1233-40.   Free full text
Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Selzner M1, Bielawska A, Morse MA, Rüdiger HA, Sindram D, Hannun YA, Clavien PA.
Author information      1Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.

Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogues in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a > 50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogues and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.

Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogues in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a >50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogues and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.
Previous SectionNext Section
INTRODUCTION  Metastatic colorectal cancer is common with ~100,000 new cases diagnosed each year in the United States (1 , 2) . Less than 20% of patients with metastatic colorectal cancer are candidates for curative surgery, and conventional chemotherapy is only marginally effective (3 , 4) . As a result, this condition has a dismal prognosis, warranting the development of new therapeutic strategies (5) .
Induction of apoptosis in tumor cells, a form of physiological death in unwanted or dysfunctional cells, is an appealing therapeutic approach (6) . Escape from apoptotic signals often accompanies tumor progression. For example, Naik et al. (7) showed in a mouse model that progression of islet cell tumors is associated with reduced susceptibility to apoptotic stimuli. Several groups have reported a higher incidence of tumor development in mice with genetic alterations of apoptotic mediators, such as Bcl-2 overexpression or Fas ligand deletion (8) . Furthermore, the response to chemo- or radiation therapy in some cancers correlates with the induction of apoptosis within the tumors (9 , 10) . These findings suggest that dysregulation of the apoptotic pathway might be a pivotal point in the genesis of a variety of cancers. Although the mechanisms and mediators of apoptosis in malignant cells remain under investigation, restoration of the physiological death pathway holds promise as a novel treatment strategy for cancer (11, 12, 13) .
Ceramide, a bioactive lipid arising from the hydrolysis of sphingomyelin or from de novo formation, has been proposed to play important roles in growth arrest, differentiation, and apoptosis in several cell culture models (14, 15, 16, 17) . For example, inhibition of ceramide formation with fumonisin B1 has been shown to prevent apoptosis in response to CPT11 and in response to angiotensin II (18 , 19) . Also, mice knocked out in acid sphingomyelinase show specific defects in endothelial and liver cell apoptosis (20 , 21) . Intracellular targets of ceramide are ceramide-activated phosphatases and ceramide-activated kinases, which in turn activate the apoptotic pathways, SAPK/JNK 3 and the caspase cascade (17 , 22) .

free pdf

Ceramide and the Induction of Apoptosis 1
W. David Jarvis, Steven Grant, and Richard N. Kolesnick 2 Departments of Medicine [W. D. J., S. G.] and Pharmacology/Toxicology [S. G.], Medical College of Virginia, Richmond, Virginia 23298-0230, and Department of Medicine and
Program of Molecular Pharmacology, Memorial Sloan-Kettering
Cancer Center, New York, New York 10021 [R. N. K.]

Apoptosis represents the subtractive component
of the physiological regulation of tissue mass [originally
referred to as regressive or shrinkage necrosis (5)], and thus is
viewed as a natural counterpart of mitosis. Apoptosis results
from activation of a preprogrammed pathway of biochemical
events that lead to cell death.

Early studies provided evidence that TNF-induced ceramide
generation mediated activation of the M r 42,000 form of the
serine/threonine protein kinase MAP kinase (also known as
ERK) (27, 28). MAP kinase participates in a protein kinase
cascade from the cell surface involving sequential phosphorylation
and activation of Raf-1 or MEKK and MEK.

http://www.ncbi.nlm.nih.gov/pubmed/21336992
Childs Nerv Syst. 2011 Apr;27(4):671-9. doi: 10.1007/s00381-011-1410-4. Epub 2011 Feb 20.
Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas–possible role of Cannabis inhalation.
Foroughi M1, Hendson G, Sargent MA, Steinbok P.
1Division of Pediatric Neurosurgery, Department of Surgery, BC Children’s Hospital, 4480 Oak Street, Vancouver, BC, Canada, V6H 3V4.
Spontaneous regression of pilocytic astrocytoma after incomplete resection is well recognized, especially for cerebellar and optic pathway tumors, and tumors associated with Neurofibromatosis type-1 (NF1). The purpose of this report is to document spontaneous regression of pilocytic astrocytomas of the septum pellucidum and to discuss the possible role of cannabis in promoting regression.
CASE REPORT:We report two children with septum pellucidum/forniceal pilocytic astrocytoma (PA) tumors in the absence of NF-1, who underwent craniotomy and subtotal excision, leaving behind a small residual in each case. During Magnetic Resonance Imaging (MRI) surveillance in the first three years, one case was dormant and the other showed slight increase in size, followed by clear regression of both residual tumors over the following 3-year period. Neither patient received any conventional adjuvant treatment. The tumors regressed over the same period of time that cannabis was consumed via inhalation, raising the possibility that the cannabis played a role in the tumor regression.
CONCLUSION:We advise caution against instituting adjuvant therapy or further aggressive surgery for small residual PAs, especially in eloquent locations, even if there appears to be slight progression, since regression may occur later. Further research may be appropriate to elucidate the increasingly recognized effect of cannabis/cannabinoids on gliomas.

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Patent GW Pharm Jul 2014

Phytocannabinoids in the treatment of cancer
US 8790719 B2
Abstract
This invention relates to the use of phytocannabinoids, either in an isolated form or in the form of a botanical drug substance (BDS) in the treatment of cancer. Preferably the cancer to be treated is cancer of the prostate, cancer of the breast or cancer of the colon.

Publication number    US8790719 B2
Publication type    Grant
Application number    US 13/634,343
PCT number    PCT/GB2011/050487
Publication date    Jul 29, 2014
Filing date    Mar 11, 2011
Priority date    Mar 12, 2010
Also published as    CA2792722A1, 4 More »
Inventors    Daniela Parolaro, Paola Massi, Angelo Antonio Izzo, Francesca Borelli, Gabriella Aviello, Vincenzo Di Marzo, Luciano De Petrocellis, Aniello Schiano Moriello, Alessia Ligresti, Ruth Alexandra Ross, Lesley Ann Ford, Sharon Anavi-Goffer, Manuel Guzman, Guillermo Velasco, Mar Lorente, Sofia Torres, Tetsuro Kikuchi, Geoffrey Guy, Colin Stott, Stephen Wright, Alan Sutton, David Potter, Etienne De Meijer, Less «
Original Assignee    Gw Pharma Limited, Otsuka Pharmaceutical Co., Limited