Cannabinoids May Inhibit Prostate Cancer Cell Growth

Published by Jan

 

Prostate Cancer-

                                    

                           

                                                          

every man should have an examination every year!


Prostate cancer is cancer that starts in the prostate gland.  The prostate is a small, walnut-sized structure that makes up part of a man's reproductive system.  It wraps around the urethra, the tube that carries urine out of the body.


Prostate Cancer Overview


What is prostate cancer?  Prostate cancer occurs when cells in the prostate gland grow out of control.  There are often no early prostate cancer symptoms, but some men have urinary symptoms and discomfort.  Prostate cancer treatment options are surgery, chemotherapy, cryotherapy, hormonal therapy, and/or radiation.  In some instances, doctors recommend "watchful waiting”.
There are no warning signs or symptoms of early prostate cancer.  Once a malignant tumor causes the prostate gland to swell significantly, or once cancer spreads beyond the prostate, the following symptoms may be present:


• A frequent need to urinate, especially at night.
• Difficulty starting or stopping a stream of urine.
• A weak or interrupted urinary stream.
• Inability to urinate standing up.
• A painful or burning sensation during urination


Symptoms


The PSA blood test is often done to screen men for prostate cancer.  Because of PSA testing, most prostate cancers are now found before they cause any symptoms.
The symptoms listed below can occur with prostate cancer (Most of the time these symptoms are caused by other prostate problems that are not cancer):
• Delayed or slowed start of urinary stream
• Dribbling or leakage of urine, most often after urinating
• Slow urinary stream
• Straining when urinating, or not being able to empty out all of the urine
• Blood in the urine or semen
• Bone pain or tenderness, most often in the lower back and pelvic bones (only when the cancer has spread)


,Causes, incidence and risk factors


Prostate cancer is the third most common cause of death from cancer in men of all ages and is the most common cause of death from cancer in men over age seventy-five.  Prostate cancer is rarely found in men younger than forty.
People who are at higher risk include:
• African-American men, who are also likely to develop cancer at every age
• Men who are older than 60
• Men who have a father or brother with prostate cancer
Other people at risk include:
• Men exposed to agent orange exposure
• Men who abuse alcohol
• Farmers
• Men who eat a diet high in fat, especially animal fat
• Tire plant workers
• Painters
• Men who have been exposed to cadmium


The lowest number of cases occurs in Japanese men living in Japan (this benefit is lost after one generation of living in the U.S.) and those who do not eat meat (vegetarians).  A common problem in almost all men as they grow older is an enlarged prostate (benign prostatic hyperplasia, or BPH).  This problem does not raise your risk of prostate cancer.

 

Signs and tests


Prostate biopsy is the only test that can confirm the diagnosis.  Tissue from the prostate is viewed underneath a microscope.  Biopsy results are reported using something called a Gleason grade and a Gleason score.
The Gleason grade is how aggressive the prostate cancer might be.  It grades tumors on a scale of (1 – 5), based on how different from normal tissue the cells are.
Often, more than one Gleason grade is present within the same tissue sample.  The Gleason grade is therefore used to create a Gleason score by adding the two most predominant grades together (a scale of 2 - 10).  The higher the Gleason score, the more likely the cancer is to have spread beyond the prostate gland:
• Scores 2 - 4: Low-grade cancer
• Scores 5 - 7: Intermediate- (or in the middle-) grade cancer.  Most prostate cancers fall into this category.
• Scores 8 - 10: High-grade cancer (poorly-differentiated cells)


There are two reasons your doctor may perform a prostate biopsy:

  • • Your PSA blood test is high.
  • • A rectal exam may show a large prostate or a hard, irregular surface.  Because of PSA, testing, prostate cancer is diagnosed during a rectal exam much less often.

The PSA blood test will also be used to monitor your cancer after treatment.  Often, PSA levels will begin to rise before there are any symptoms.  An abnormal digital rectal exam may be the only sign of prostate cancer (even if the PSA is normal).
The following tests may be done to determine whether the cancer has spread:
• CT scan
• Bone scan


Treatment


The best treatment for your prostate cancer may not always be clear.  Sometimes, your doctor may recommend one treatment because of what is known about your type of cancer and your risk factors.  Other times, your doctor will talk with you about two or more treatments that could be good for your cancer.
In the early stages, talk to your doctor about several options, including surgery and radiation therapy.  In older patients, simply monitoring the cancer with PSA tests and biopsies may be an option.
Prostate cancer that has spread may be treated with drugs to reduce testosterone levels, surgery to remove the testes, or chemotherapy.
Surgery, radiation therapy, and hormonal therapy can interfere with sexual desire or performance.  Problems with urine control are common after surgery and radiation therapy.  These problems may either improve over time or get worse, depending on the treatment.  Discuss your concerns with your health care provider.
SURGERY
Surgery is usually only recommended after a thorough evaluation and discussion of the benefits and risks of the procedure.
• Surgery to remove the prostate and some of the tissue around it is an option when the cancer has not spread beyond the prostate gland.  This surgery is called radical prostatectomy.  It can also be done with robotic surgery.
• Possible problems after the surgeries include difficulty controlling urine or bowel movements and erection problems.
RADIATION THERAPY
Radiation therapy uses high-powered x-rays or radioactive seeds to kill cancer cells.
Radiation therapy works best to treat prostate cancer that has not spread outside of the prostate.  It may also be used after surgery, if there is a risk that prostate cancer cells may still be present.  Radiation is sometimes used for pain relief when cancer has spread to the bone.
External beam radiation therapy uses high-powered x-rays pointed at the prostate gland.
• It is done in a radiation oncology center usually connected to a hospital.  You will come to the center from home 5 days a week for the treatments.  The therapy lasts for six -8 weeks.
• Before treatment, a therapist will mark the part of the body that is to be treated with a special pen.
• The radiation is delivered to the prostate gland using a device that looks like a normal x-ray machine.  The treatment itself is generally painless.
• Side effects may include impotence, incontinence, appetite loss, fatigue, skin reactions, rectal burning or injury, diarrhea, bladder urgency, and blood in urine.
Prostate brachytherapy involves placing radioactive seeds inside the prostate gland.
• A surgeon inserts small needles through the skin behind your scrotum to inject the seeds.  The seeds are so small that you do not feel them.  They can be temporary or permanent.
• Brachytherapy is often used for men with smaller prostate cancer that is found early and is slow growing.
• It also may be given with external beam radiation therapy for some patients with more advanced cancer.
• Side effects may include pain, swelling or bruising in your penis or scrotum, red-brown urine or semen, impotence, incontinence, and diarrhea.
Proton therapy is another kind of radiation used to treat prostate cancer.  Doctors aim proton beams onto a tumor, so there is less damage to the surrounding tissue.
HORMONE THERAPY
Testosterone is the body's main male hormone.  Prostate tumors need testosterone to grow.  Hormonal therapy is any treatment that decreases the effect of testosterone on prostate cancer.  These treatments can prevent further growth and spread of cancer.
Hormone therapy is mainly used in men whose cancer has spread to help relieve symptoms.  There are two types of drugs used for hormone therapy.
The primary type is called a luteinizing hormone-releasing hormones (LH-RH) agonist:
• These medicines block the body from making testosterone.  The drugs must be given by injection, usually every 3 - 6 months.
• They include leuprolide, goserelin, nafarelin, triptorelin, histrelin, buserelin, and degarelix.
• Possible side effects include nausea and vomiting, hot flashes, anemia, lethargy, osteoporosis, reduced sexual desire, decreased muscle mass, weight gain, and impotence.
The other medications used are called androgen-blocking drugs.
• They are often given along with the above drugs.
They include flutamide, bicalutamide, and nilutamide.
Possible side effects include erectile dysfunction, loss of sexual desire, liver problems, diarrhea, and enlarged breasts.
The testes make much of the body’s testosterone.  As a result, removal of the testes (called orchiectomy) can also be used as a hormonal treatment.  This surgery is not done very often.
Chemotherapy and immunotherapy are used to treat prostate cancers that no longer respond to hormone treatment.  An oncology specialist will usually recommend a single drug or a combination of drugs.
MONITORING
After treatment for prostate cancer, you will be closely watched to make sure the cancer does not spread.  This involves routine doctor check-ups, including serial PSA blood tests (usually every 3 months to 1 year).

 

Expectations (prognosis)


The outcome varies greatly.  It is mostly affected by whether the cancer has spread outside the prostate gland and how abnormal the cancer cells are (the Gleason score) when you are diagnosed.
Many patients with prostate cancer that has not spread can be cured, as well as some patients whose cancer has not spread very much outside the prostate gland.
Even for patients who cannot be cured, hormone treatment can extend their life by many years.

 

Prevention


Following a vegetarian, low-fat diet or one that is similar to the traditional Japanese diet may lower your risk.  This would include foods high in omega-3 fatty acids.
Finasteride (Proscar, generic) and dutasteride (Avodart) are drugs used to treat benign prostatic hyperplasia (BPH).
The American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) recommend that doctors discuss the pros and cons of these drugs with men who:
• Have a PSA score of 3.0 or below
• Are being screened yearly for prostate cancer
• Do not yet show signs of prostate cancer
Not all experts agree with this recommendation.

 

Cannabinoids May Inhibit Prostate Cancer Cell Growth


Research:
Inhibition of human tumor prostate PC-3 cell growth by cannabinoids R (+)-Methanandamide and JWH-015: Involvement of CB2
background:
 
We have previously shown that cannabinoids induce growth inhibition and apoptosis in prostate cancer PC-3 cells, which express high levels of cannabinoid receptor types 1 and 2 (CB1 and CB2).  In this study, we investigated the role of CB2 receptor in the anti-proliferative action of cannabinoids and the signal transduction triggered by receptor ligation.
results:
 
We found that the anandamide analogue, R(+)-Methanandamide (MET), as well as JWH-015, a synthetic CB2 agonist, exerted anti-proliferative effects in PC-3 cells.  R (+)-Methanandamide- and JWH-015-induced cell death was rescued by treatment with the CB2 receptor antagonist, SR 144528.  Down regulation of CB2, expression reversed the effects of JWH-015, confirming the involvement of CB2 in the pro-apoptotic effect of cannabinoids.  Further analyzing the mechanism of JWH-015-induced cell growth inhibition, we found that JWH-015 triggered a de novo synthesis of ceramide, which was involved in cannabinoid-induced cell death, insofar as blocking ceramide synthesis with Fumonisin B1 reduced cell death.  Signaling pathways activated by JWH-015 included JNK (c-Jun N-terminal kinase) activation and Akt inhibition.  In vivo treatment with JWH-015 caused a significant reduction in tumor growth in mice.
conclusions: 
This study defines the involvement of CB2-mediated signaling in the in vivo and in vitrogrowth inhibition of prostate cancer cells and suggests that CB2 agonists have potential therapeutic interest and deserve to be explored in the management of prostate cancer.
Cannabinoids: potential anticancer agents
Manuel Guzmán
Abstract
Cannabinoids — the active components of Cannabis sativa and their derivatives — exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite.  In addition, these compounds have been shown to inhibit the growth of tumor cells in culture and animal models by modulating key cell-signaling pathways.  Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies.  So, could cannabinoids be used to develop new anticancer therapies?

The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis
Two main molecular targets of  -9-tetrahydrocannabinol (THC), the psychoactive principle of Cannabis sativa, are type 1 and type 2 cannabinoid receptors (CB1R and CB2R).  Both of them were discovered and characterized more than four millennia after the beneficial effects of cannabis extracts had been exploited in folklore medicine.  Afterwards, an endogenous THC-like molecule, called anandamide (N-arachidonoylethanolamine; AEA) from 'ananda', the Sanskrit word for 'bliss', was isolated and found to activate CB receptors, thus mimicking the psychotropic effects of THC.  In a few years other endogenous agonists of CB receptors were characterized, and were collectively called 'endocannabinoids'.  Recently, the biological actions of the endocannabinoids and their implications for human health have been reviewed.  In particular, attention has been focused on the possible role of AEA and other endocannabinoids in regulating cell growth and differentiation, which might account for some pathophysiological effects of these lipids.  This paper will focus on the metabolism of AEA and its involvement in apoptosis, and more generally, it will discuss the ability of AEA to control cell fate.

CB2 Cannabinoid Receptor-mediated Regulation of Prostate Cancer Growth
Prostate cancer is a major health problem and a significant cause of mortality in men worldwide.  Family history and race are the two major risk factors for this disease.  The age-adjusted incidence rate and mortality rate of prostate cancer is significantly higher in African-Americans compared to Caucasian-Americans or other races in the US and worldwide.  Thus, an understanding of the molecular mechanism responsible for the development and progression of prostate cancer is extremely important to the development of more effective therapeutic strategies.  Cannabinoids (including endocannabinoids) regulate cell death or cell growth, depending on the cell type and concentration of the cannabinoid.  Cannabinoids inhibit the growth of prostate cancer cells.  We have found that activation of cannabinoid receptor-2 (CB2) inhibits androgen-sensitive prostate cancer (AS PC) cell proliferation and motility.  Our preliminary data also suggest that cannabinoid compounds possess selective efficacy, producing less adverse effects on normal prostate epithelial cells compared to LNCaP prostate cancer cells.  To date most of the anti-tumor effects of cannabinoids have been correlated with the CB1 receptors rather than CB2 receptor activation, although CB2 receptor expression is high in many tumor tissues including prostate tumor.  However, downstream mechanisms mediating anti-tumor effects of cannabinoids under in vivo conditions are poorly understood.  Further, CB1 receptors are highly expressed in neuronal cells and brain tissue.  Therefore, unlike activation of CB2 receptors, CB1 receptor activation produces neurobehavioral and psychotropic side effects.  Thus, CB2 receptor-mediated therapeutic intervention of prostate cancer has clinical advantages.  Based on our preliminary data we hypothesize that activation of CB2 receptor inhibits androgen-sensitive prostate cancer (AS PC) growth.  To test this hypothesis, we have developed the following 2 specific aims: (1) To determine the effects of CB2 receptor activation on cultured LNCaP and LAPC4 prostate cancer cell proliferation, viability and migration in relation to activation of RhoA and the focal adhesion kinase (FAK) signaling pathway; and (2) To determine the effects of exogenous activation of CB2 receptor and increase in endogenous cannabinoid activity on AS prostate cancer growth in mice in relation to FAK activity.

Cannabinoids Offer Novel Approach for Treatment of Prostate Cancer,
Madison, WI: The administration of synthetic cannabinoids inhibits malignant cell growth in human prostate cells in vitro in a dose-dependent and time-dependent manner, according to clinical trial data published in the March issue of the journal Cancer Research.
Researchers at University of Wisconsin's Department of Dermatology reported that the administration of the cannabis receptor agonist WIN-55,212-2 inhibited cell growth in certain human prostate cells, and induced apoptosis (programmed cell death).  Administration of a cannabis receptor antagonist prevented these effects.
"Our results suggest that ... cannabinoid receptor agonists (a drug or chemical that combines with a receptor to produce a physiological reaction typical of a naturally occurring substance) could be developed as novel therapeutic agents for the treatment of prostate cancer," authors concluded.
Previous trials have found cannabinoids to induce tumor regression in rodents and in human cells, including the inhibition of lung carcinoma, glioma (brain tumors), lymphoma/leukemia, skin carcinoma, and breast cancer.

Cannabis chemicals may help fight prostate cancer
Reuters) - Chemicals in cannabis have been found to stop prostate cancer cells from growing in the laboratory, suggesting that cannabis-based medicines could one-day help fight the disease, scientists said Wednesday.
After working initially with human cancer cell lines, Ines Diaz-Laviada and colleagues from the University of Alcala in Madrid also tested one compound on mice and discovered it produced a significant reduction in tumor growth.
Their research, published in the British Journal of Cancer, underlines the growing interest in the medical use of active chemicals called cannabinoids, which are found in marijuana.
Experts, however, stressed that the research was still exploratory and many more years of testing would be needed to work out how to apply the findings to the treatment of cancer in humans.
"This is interesting research which opens a new avenue to explore potential drug targets but it is at a very early stage," said Lesley Walker, director of cancer information at Cancer Research UK, which owns the journal.
"It absolutely isn't the case that men might be able to fight prostate cancer by smoking cannabis," she added
The cannabinoids tested by the Spanish team are thought to work against prostate cancer because they block a receptor, or molecular doorway, on the surface of tumor cells.  This stops them from dividing.
In effect, the cancer cell receptors can recognize and "talk to" chemicals found in cannabis, said Diaz-Laviada.
"These chemicals can stop the division and growth of prostate cancer cells and could become a target for new research into potential drugs to treat prostate cancer," she said.
Her team's work with two cannabinoids -- called methanandamide and JWH-015 -- is the first demonstration that such cannabis chemicals prevent cancer cells from multiplying.
Some drug companies are already exploring the possibilities of cannabinoids in cancer, including British-based cannabis medicine specialist GW Pharmaceuticals.
It is collaborating with Japan's Otsuka on early-stage research into using cannabis extracts to tackle prostate cancer -- the most commonly diagnosed cancer in men -- as well as breast and brain cancer.
GW has already developed an under-the-tongue spray called Sativex for the relief of some of the symptoms of multiple sclerosis, which it plans to market in Europe with Bayer and Almirall.
Other attempts to exploit the cannibinoid system have met with mixed success.  Sanofi-Aventis was forced to withdraw its weight-loss drug Acomplia from the market last year because of links to mental disorders.

Cannabinoid receptors agonist WIN-55,212-2 inhibits angiogenesis, metastasis and tumor growth of androgen-sensitive prostate cancer cell CWR22R1 xenograft in athymic nude mice
Cannabinoids and their receptors agonists are drawing renewed attention as potential anti-tumor agents.  Recently, we have shown that expression levels of both cannabinoid receptors CB1 and CB2 are higher in human prostate cancer cells than in normal prostate epithelial cells (Cancer Res. 65:1635-41, 2005) and observed that sustained activation of ERK1/2 by cannabinoid receptors agonist WIN-55,212-2 (WIN) leads to G1 cell cycle arrest and apoptosis in LNCaP cells (J. Biol. Chem., PMID: 17068343).  To establish in vivo relevance of these in vitro findings, we implanted athymic nude mice with androgen-responsive CWR22R1 cells, which form rapid tumors and secrete PSA in the blood stream of the host.  As compared to untreated animals, WIN treated mice (0.5 mg/kg b.wt, i.p, alternate day) exhibited significant inhibition in the tumor growth with significant reduction in PSA secretion in the serum.  In animals without WIN treatment, targeted tumor volume of 1200 mm3 was reached at 35 days post-tumor inoculation;  whereas this tumor volume was attained in 51 days in WIN treated mice.  Since angiogenesis is an essential component to primary tumor growth and metastasis, we next assessed the effect of WIN treatment on the markers of cell proliferation, angiogenesis and metastasis.  Protein expression of PCNA, a marker of cell proliferation was considerably lower (45%) in tumors of WIN treated mice as compared to untreated animals.  Protein expression of angiopoetins and VEGF, members of the vascular endothelial growth factor family that participate in the formation of blood vessels were also evaluated.  Tumor tissues from WIN treated mice had notably lower expression of both angiopoetin-1 (41%) and angiopoetin-2 (38%) and showed marked decrease (47%) in the expression of VEGF positive cells.  Loss of function of E-cadherin is associated with progression of cancer by increasing proliferation, invasion, and/or metastasis.  We observed that in WIN treated mice E-cadherin expression was (2.5) fold higher as compared to untreated animals.  We also found a decrease in the protein expression of cadherin associated proteins β-catenin and -catenin in tumors of mice treated with WIN.  In the next series of experiments, we determined the effect of WIN on the expression of proteins involved in metastasis.  The balance between matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) is an essential factor in the aggressiveness of several cancers.  We observed that MMP to TIMP ratio in WIN treated mice was tilted towards TIMP expression suggesting inhibition of MMP expression.  Here, we provide in vivo evidence for potential use of cannabinoid receptors agonist for slowing tumor growth of androgen sensitive cells in a xenograft model.

www.youtube.com/watch?v=ALLN-Np9fwk

Cannabinoids May Help Shrink Prostate Cancer Tumors
Chemicals found in marijuana could be linked to a possible cure for prostate cancer.
Ines Diaz-Laviada and colleagues from the University of Alcala in Madrid found that chemicals in cannabis stopped the growth of prostate cancer cells in laboratory tests.
Additionally, researchers found that the chemicals derived from cannabis helped shrink the size of prostate cancer tumors in mice.
“Cannabinoids can stop the division and growth of prostate cancer cells and could become a target for new research into potential drugs to treat prostate cancer”, ? Diaz-Laviada and colleagues wrote in the British Journal of Cancer.
Researchers believe the cannabinoids — methanandamide and JWH-015 ““work against prostate cancer by blocking a receptor on the surface of tumor cells.
"Our research shows that there are areas on prostate cancer cells that can recognize and talk to chemicals found in cannabis called cannabinoids,”? said Diaz-Laviada.
However, Lesley Walker, director of cancer information at Cancer Research UK, said that the study does not prove that “men might be able to fight prostate cancer by smoking cannabis."
"This is interesting research which opens a new avenue to explore potential drug targets but it is at a very early stage," said Walker.
According to Reuters, drug companies have been studying the impacts of cannabinoids in cancer prevention and control.
British-based cannabis medicine specialist GW Pharmaceuticals has been working alongside Japan’s Otsuka with researching the use of cannabinoids in the treatment of prostate, breast and brain cancer.


Cannabinoids in the treatment of cancer
Cannabinoids regulate cell survival pathways
The role of JWH-133, a CB2 selective agonist, as an anticancer agent
The role of WIN 55,212-2, a CB1/CB2 non-selective agonist, as an anticancer agent
Conclusions:
The majority of the literature demonstrates that various cannabinoids inhibit cancer cell growth in vitro and tumor growth in vivo and that the induction of apoptosis plays a major role in the mechanism for this effect.  The potency of this effect varies with each cannabinoid.  Therefore, the differences in binding properties at the cannabinoid receptors may result in different downstream effects.  For example, partial agonism at the cannabinoid receptors by D9-THC or AEA compared to potent full agonism at the cannabinoid receptors by the synthetic cannabinoids JWH-133 or WIN 55,212-2, could lead to a divergence of downstream signaling that could produce altered responses in cell growth.  The full potential of these synthetic cannabinoids has yet to be determined and there is a need for much more extensive research into the dose-response relationships as well as the mechanisms elicited by the speci?c cannabinoids if cannabinoids are going to be further developed into potential cancer treatments.

Controversy regarding the anti-cancer actions of cannabinoids
Although the consensus in the current literature indicates that cannabinoids have anti-cancer effects, a few studies have shown that D9-THC has a biphasic effect in cancer cells, where lower concentrations result in an increase in proliferation of cancer cells and higher concentrations cause a decrease in cell proliferation.  For example, D9-THC at 100–300 no elicited a 1.2 and 2-fold increase in the proliferation rate of NCl-H292 (lung cancer) and U373-MG (glioblastoma) cells, respectively D9 -THC (4–
10 lM) were cytotoxic and i.  In contrast, higher concentrations of D9 increased the number of apoptotic cells (30–80%).  Similarly, Sanchez et al demonstrated that D 9-THC (50-100 nM) increased the pro-
liferation and viability of androgen-independent prostate cancer cells (PC3), while Ligresti et al. demonstrated that higher concentrations of D9 -THC inhibited the proliferation of MDA-MB-231 breast cancer cells.  This increase in cell proliferation in vitro has also been supported by in vivo studies.  However, the increase in tumor growth was elicited by higher doses of D9 -THC.  Speci?cally, McKallip et al. demonstrated that D9-THC (25 mg/kg and 50 mg/kg i.p. every other d, 21 d) caused 2-fold increase in tumor volume compared to vehicle control in female BALB/c mice bearing murine mammary 4T1 tumors.  However, when they repeated the study in SCID-NOD mice, which are devoid of an immune response, 9-THC (25 mg/kg i.p. every other d, 19 d) did not alter tumor volume compared to vehicle treated animals.  
They hypothesized that these effects were probably due to a D9-THC-mediated inhibition of a speci?c anti-tumor immune response.  It is well known that cannabinoids may cause suppression of the immune system via CB2 activation and Xu et al. found that JWH-133 cause. . .

The cannabinoid R+ methanandamide induces IL-6 secretion by prostate cancer PC3 cells.
In the present study, we have investigated the effect of the cannabinoid R+ methanandamide (MET) in the androgen-resistant prostate cancer PC3 cells.  MET induced a dose-dependent decrease in PC3 cell viability as well as a dose-dependent increase in the secretion of the cytokine IL-6.  Looking deeper into the mechanisms involved, we found that MET-induced de novo synthesis of the lipid mediator ceramide that was blocked by the ceramide synthase inhibitor Fumonisin B1.  Pre-incubation of cells with the cannabinoid receptor CB2 antagonist SR 144528 (SR2), but not the CB1 antagonist Rimonabant or the TRPV1 antagonist capsazepine, partially prevented the anti-proliferative effect, the ceramide accumulation, and the IL-6-induced secretion, suggesting a CB2 receptor-dependent mechanism.  Fumonisin B1 did not have any effect in the IL-6 secretion increase induced by MET.  However, even an incomplete down-regulation of (i.e., not a total silencing of) ceramide kinase expression by specific siRNA prevented the MET-induced IL-6 secretion.  These results suggest that MET regulates ceramide metabolism in prostate PC3 cells that is involved in cell death as well as in IL-6 secretion.  Our findings also suggest that CB2 agonists may offer a novel approach in the treatment of prostate cancer by decreasing cancer epithelial cell proliferation.  However, the interaction of prostate cancer cells with their surrounding, and in particular with the immune system in vivo, needs to be further explored.

The cannabinoid JWH-015 activates NF?B in prostate cancer PC-3 cells: Involvement of CB2 and PI3K/Akt
In recent years, much progress has been done about the role of Cannabis sativa derived compounds on the regulation of cell proliferation.  In particular, cannabinoids have shown the ability to inhibit the growth of prostate cancer cells in vitro and in vivo.  Cannabinoids bind to two types of GPCR receptors named CB1 and CB2.  Whereas CB1 is mainly found in central nervous system and mediates the psychotropic actions of cannabinoids, CB2 has been mostly found in peripheral and immune tissues.  Androgen-resistant prostate cancer PC-3 cells express both cannabinoid receptors although only CB2 is clearly involved in the anti-tumoral effect of cannabinoids on PC-3 cells.
In this study, we have used the CB2 selective agonist JWH-015 to analyze the signaling mechanisms activated in PC-3 cells.
Main conclusion: We have found that JWH-015 induces the secretion of IL-6 to the PC-3 culture supernatant that was blocked by the PI3K inhibitor LY 294002 as well as by the CB2 antagonist SR 144258.  In line with these results, incubation of PC-3 cells with JWH-015 increased the levels of Akt phosphorylation that was reversed by SR144285.  Treatment of PC-3 cells with JWH-015 resulted in an increase in the phosphorylation of I?Bα as well as a translocation of p65 to the nucleus.  This phenomenon was reversed by LY 294002 and by SR 144258.  Moreover, the secretion of IL-6 in cannabinoid-treated cells was abrogated by the pre-incubation with the IKKβ inhibitor, BAY11-7082.
Taking together this findings suggest that the cannabinoid JWH-015 induces IL-6 secretion by a mechanism involving CB2, PI3K/Akt and NF?B activation.

Recommendation:

More research and more clinical studies are necessary.  From what I can evaluate, cannabis is the obvious adjunct treatment for prostate cancer.
Use whole plant extracts:  Indica x Sativa hybrids
Oils, tinctures, concoctions, cannabutter, edibles, spray, under the tongue, vaporizer, and suppositories.
Objective:  get the medicine into the system as soon as possible.

 

 


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References:
1. Andriole GL, Crawford ED, Grubb RI 3rd, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319.
2. Babaian RJ, Donnelly B, Bahn D, Baust JG, Dineen M, Ellis D, et al. Best practice statement on cryosurgery for the treatment of localized prostate cancer. J Urol. 2008;180:1993-2004.
3. NCCN Clinical Practice Guidelines in Oncology: Prostate cancer. V.2.2009. Accessed June 2009.
4. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328.
5. Walsh PC, DeWeese TL, et al. Clinical practice: localized prostate cancer. N Engl J Med. 2007;357(26):2696-2705.
6. Walsh PC. Chemoprevention of prostate cancer. N Engl J Med. 2010 Apr 1;362(13):1237-8.
7. Wilt TJ, MacDonald R, et al. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med. 2008;148(6):435-448.
[1] D. Gaoni, R. Mechoulam, Isolation, structure and partial synthesis of
an active constituent of hashish, J. Am. Chem. Soc. 86 (1964) 1646–
1647.
[2] M.A. Elsohy, D. Slade, Chemical constituents of marijuana: the
complex mixture of natural cannabinoids, Life Sci. 78 (2005) 539–
548.
[3] W.A. Devane, L. Hanus, A. Breuer, R.G. Pertwee, L.A. Stevenson, G.
Grif?n, D. Gibson, A. Mandelbaum, A. Etinger, R. Mechoulam,
Isolation and structure of a brain constituent that binds to the
cannabinoid receptor, Science 258 (1992) 1946–1947.
[4] R.I. Wilson, R.A. Nicoll, Endocannabinoid signaling in the brain,
Science 296 (2002) 678–682.
[5] A.C. Howlett, F. Barth, T.I. Bonner, G. Cabral, P. Casellas, W.A. Devane,
C.C. Felder, M. Herkenham, K. Mackie, B.R. Martin, R. Mechoulam,
R.G. Pertwee, International union of pharmacology. XXVII.
Classi?cation of cannabinoid receptors, Pharmacol. Rev. 54 (2002)
161–202.
[6] L.A. Matsuda, S.J. Lolait, M.J. Brownstein, A.C. Young, T.I. Bonner,
Structure of a cannabinoid receptor and functional expression of the
cloned cDNA, Nature 346 (1990) 561–564.
[7] S. Munro, K.L. Thomas, M. Abu-Shaar, Molecular characterization of a
peripheral receptor for cannabinoids, Nature 365 (1993) 61–65.
[8] C.C. Felder, M. Glass, Cannabinoid receptors and their endogenous
agonists, Ann. Rev. Pharmacol. Toxicol. 38 (1998) 179–200.
[9] R.G. Pertwee, Cannabinoid pharmacology: the ?rst 66 years, Br. J.
Pharmacol. 147 (2006) S163–S171.
[10] M. Guzman, Cannabinoids: potential anticancer agents, Nat. Rev.
Cancer 3 (2003) 745–755.
[11] S. Sarfaraz, V.M. Adhami, D.N. Syed, F. Afaq, H. Mukhtar,
Cannabinoids for cancer treatment: progress and promise, Cancer
Res. 2008 (2008) 339–342.
[12] M. Glass, J.K. Northup, Agonist selective regulation of G proteins by
cannabinoid CB1 and CB2 receptors, Mol. Pharmacol. 56 (1999)
1362–1369.
[13] D.G. Demuth, A. Molleman, Cannabinoid signalling, Life Sci. 78
(2006) 549–563.
[14] M.R. Tramer, D. Carroll, F.A. Campbell, J.M. Reynolds, R.A. Moore,
Cannabinoids for control of chemotherapy induced nausea and
vomiting: quantitative systematic review, Br. Med. J. 323 (2001) 16–
21.
[15] A.E. Munson, L.S. Harris, M.A. Friedman, W.L. Dewey, R.A. Carchman,
Antineoplastic activity of cannabinoids, J. Natl. Cancer Inst. 55
(1975) 597–602.
[16] I. Galve-Roperh, C. Sanchez, M.L. Cortez, T. Gomez del Pulgar, M.
Izquierdo, M. Guzman, Antitumoral action of cannabinoids:
involvement of sustained ceramide accumulation and extracellular
signal-regulated kinase activation, Nat. Med. 6 (2000) 313–319.
[17] C. Sanchez, M.L. de Caballos, T. Gomez del Pulgar, D. Rueda, C.
Corbacho, G. Velasco, I. Galve-Roperh, J.W. Huffman, S.R. Cajal, M.
cannabinoid receptor, Science 258 (1992) 1946–1947.
[4] R.I. Wilson, R.A. Nicoll, Endocannabinoid signaling in the brain,
Science 296 (2002) 678–682.
[5] A.C. Howlett, F. Barth, T.I. Bonner, G. Cabral, P. Casellas, W.A. Devane,
C.C. Felder, M. Herkenham, K. Mackie, B.R. Martin, R. Mechoulam,
R.G. Pertwee, International union of pharmacology. XXVII.
Classi?cation of cannabinoid receptors, Pharmacol. Rev. 54 (2002)
161–202.
[6] L.A. Matsuda, S.J. Lolait, M.J. Brownstein, A.C. Young, T.I. Bonner,
Structure of a cannabinoid receptor and functional expression of the
cloned cDNA, Nature 346 (1990) 561–564.
[7] S. Munro, K.L. Thomas, M. Abu-Shaar, Molecular characterization of a
peripheral receptor for cannabinoids, Nature 365 (1993) 61–65.
[8] C.C. Felder, M. Glass, Cannabinoid receptors and their endogenous
agonists, Ann. Rev. Pharmacol. Toxicol. 38 (1998) 179–200.
[9] R.G. Pertwee, Cannabinoid pharmacology: the ?rst 66 years, Br. J.
Pharmacol. 147 (2006) S163–S171.
[10] M. Guzman, Cannabinoids: potential anticancer agents, Nat. Rev.
Cancer 3 (2003) 745–755.
[11] S. Sarfaraz, V.M. Adhami, D.N. Syed, F. Afaq, H. Mukhtar,
Cannabinoids for cancer treatment: progress and promise, Cancer
Res. 2008 (2008) 339–342.
[12] M. Glass, J.K. Northup, Agonist selective regulation of G proteins by
cannabinoid CB1 and CB2 receptors, Mol. Pharmacol. 56 (1999)
1362–1369.
[13] D.G. Demuth, A. Molleman, Cannabinoid signalling, Life Sci. 78
(2006) 549–563.
[14] M.R. Tramer, D. Carroll, F.A. Campbell, J.M. Reynolds, R.A. Moore,
Cannabinoids for control of chemotherapy induced nausea and
vomiting: quantitative systematic review, Br. Med. J. 323 (2001) 16–
21.
[15] A.E. Munson, L.S. Harris, M.A. Friedman, W.L. Dewey, R.A. Carchman,
Antineoplastic activity of cannabinoids, J. Natl. Cancer Inst. 55
(1975) 597–602.
[16] I. Galve-Roperh, C. Sanchez, M.L. Cortez, T. Gomez del Pulgar, M.
Izquierdo, M. Guzman, Antitumoral action of cannabinoids:
involvement of sustained ceramide accumulation and extracellular
signal-regulated kinase activation, Nat. Med. 6 (2000) 313–319.
[17] C. Sanchez, M.L. de Caballos, T. Gomez del Pulgar, D. Rueda, C.
Corbacho, G. Velasco, I. Galve-Roperh, J.W. Huffman, S.R. Cajal, M.
Cajal, M.
 

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