Prostate cancer is the second most common cancer in men and the second leading cause of cancer death after lung cancer.
The number of prostate cancers found during autopsies is similar around the world, whereas the number of patients clinically evident varies greatly in different countries; in other words, it seems that “environmental factors” play a major role in the onset of the disease.
The risk of prostate cancer increases in Asian men when they emigrate to the West and embrace that lifestyle with its power, like the same thing happens in Asian women for breast cancer.
If on the one hand a diet rich in lipids, such as alpha-linoleic acid, and polycyclic aromatic hydrocarbons that are formed during the cooking of red meat increases the risk of cancer, on the other hand the daily intake of vegetables that contain the sulfurafano, factors such as genistein and retinoids isoflavonoide like lycopene tomatoes play a documented protective effect.
The clinical history of prostate cancer or the onset of a preneoplastic lesion localized prostate emergence of a symptomatic metastatic lesion to the final deadly event, can last decades and due to its long latency and the ability to diagnose pre-injury cancer in the early stages this cancer is an ideal target for chemo prevention operated with nutraceuticals.
Nutraceuticals investigated through epidemiological studies, clinical and experimental in vitro and on animals, have shown to have properties very useful for the prevention and treatment of prostate cancer, as well as other malignancies in general. Not only that, but in combination with conventional treatments could achieve the objective of significantly improve the efficacy of chemotherapy (1-2).
There are several compounds that beyond for loss of part, play a good therapeutic action of “containment” on the aforementioned neoplasia. Among many proposals polyphenols are those in clinical trials have shown some effectiveness. Epigallocatechin-3-gallate (green tea), curcumin, resveratrol (grape skin etc.), Carotenoids such as lycopene from tomatoes and flavonoids like quercetin and genistein have attracted the attention of researchers and have proven promising elements chemo prevention.
With pomegranate we enter a very interesting area because this fruit has been shown to have significant anti-tumor actions.
Punica granatum L (originating in Iran pomegranate) has significant anti-inflammatory properties on the cardiovascular system, lowers total cholesterol and protects the good (HDL) cholesterol from oxidation.
Pomegranate juice, obtained by pressing of the whole fruit, contains a high concentration of highly bioactive polyphenols called ellagitannins.
These by hydrolysis in the intestine form ellagic acid (6) and due to metabolism operated by the intestinal bacterial flora generate urolithin, highly bioactive compound, which excreted in the urine inhibits the growth of prostate cancer cells.
Among pomegranate ellagitannins the Punicalgina is the most abundant polyphenol and is responsible for more than half of the antioxidant power of the fruit (55). Furthermore, in tests carried out in vitro the pomegranate juice antioxidant shows a power superior to that of the most common fruit juices on the market (56).
On prostate cancer pomegranate plays a particular preventive action as shown by a study appearing in “Clinical Cancer Research” in 2006, in which researchers administered 240 ml / day of pomegranate juice contains 570 mg of total polyphenols in men with prostate cancer already treated by radiation therapy or surgery, but which had high levels of prostate specific antigen (PSA), which is a marker of tumor growth.
Before treatment the “average doubling time” ie the time necessary to the PSA to increase eg: from 2 to 4, was 15 months; after the treatment was 54 months !! (7).
Incidentally the doubling time of PSA is a predictor of survival in patients with prostate cancer and recurrent disease.
Also there was a decrease of tumor growth of 12%, an increase in tumor cell death by 17%, and an increase of 23% of blood levels of nitric oxide which fights cancer.
The study was conducted for two years on 40 patients with prostate cancer and progressive increase in PSA, beyond the ‘85% of the participants responded positively to the pomegranate juice (6).
Green tea and prostate cancer
The green tea that is derived from the plant Camellia Sinensis is used in the Far East for many centuries and contains polyphenolic compounds the most abundant of which is epigallocatechin-3-gallate (EGCG), a powerful antioxidant is the vitamin. And C is the vitamin. And (7).
From epidemiological observations of the low incidence of prostate cancer in those regions is attributed to the consumption of green tea.
Testosterone (male sex hormone) plays a role “permissive” in the onset of cancer, it is also likely that dietary and genetic factors may modulate blood levels of this hormone and change the course of the disease.
Androgens once in the prostate tissue will bind to the receptor on the cell surface and Androgenic place via this trigger the synthesis of proteins that regulate the proliferation and differentiation of prostate cells.
The suppression of circulating testosterone levels causes growth arrest or tumor regression.
In the course of this study you will see how certain natural substances (turmeric, genistein, lycopene, EGCG) are able to block the androgen receptor and thereby reduce the action of testosterone on tumor growth.
In this regard it is very interesting experimental observation published in the “FASEB Journal” 2011, in which it is shown that in animal models EGCG acts as a direct antagonist of androgens; physically he goes to occupy the receptor for these hormones at the level of the prostate by inhibiting their permissive action on the development of cancer (8).
remarkable results have been reported with the administration of green tea extracts orally in mice genetically programmed to develop prostate cancer. The treatment for 24 weeks was followed by the reduction of 40% of the development of localized tumor and had also prevented for a 70% metastatic spread to the lymph nodes, liver and lungs compared to control mice (9).
Major clinical study on chemo prevention, unsurpassed to this day, was executed in 2006 by a group of Italian researchers headed by Dr. Bettuzzi Parma.
They were administered 600 mg / day of green tea extract in 60 men with localized prostate cancer diagnosis, and has been studied the progression of neoplasia. These pre-malignant lesions diagnosed by ultrasound and biopsies, evolve into a considerable number of frankly malignant tumors within a year of diagnosis (10). The patients were divided into two groups of 30 men each.
In the group treated with green tea extracts after a year there has been only one case of prostate cancer, whereas in the placebo group there were 9 cases.
Statistically the effectiveness of treatment was 90% (11).
After two years was made a new assessment exactly in 2008 and despite a significant loss in patients who have not adhered most to the study, two additional cancer diagnosis appeared in the placebo group and one in the group treated with green tea. In simple words, even after cessation of treatment (the treatment lasted only the first year) who had hired in the first year of tea extracts had reduced by almost 80% in the diagnosis of prostate cancer than the placebo group (12).
THERAPY IN CHEMIOPREVENTION
Eepigallocatechin gallate cps (green tea in the form of active ingredient in the galenic formulation):
1 cps 400 mg after breakfast
1 cps 400 mg after dinner
In the cases clinically active cancer and advanced increasing dosages:
1 cps x 600 mg three times daily after meals.
240 ml after breakfast
According to the National Cancer Institute approximately 400 compounds have been identified as potential chemo preventive agents but only 40 are currently undergoing clinical evaluation.
Selenium and Vitamin E
Selenium is a nonmetallic trace element recognized as an essential nutrient for human health. Its popular antioxidant power has been proposed as the main mechanism to explain its supposed anti-cancer activity.
From many years it has been in vogue the concept that antioxidants can treat or prevent malignant tumors via the ability to inhibit the free radicals which, by damaging DNA with their mutagenic action, would result in the formation of the tumor.
This concept has lately been audited by some jobs that have shown that things do not always follow those lines of development. In a study carried out on animals and human cells in culture appeared on “Science Traslational Medicine” in 2015, it is shown that the administration of antioxidants into mice with malignant melanoma doubled the rate of metastases, in other words antioxidants not only protect healthy cells from free radicals but also those tumor (3). These harmful effects were also confirmed by tests carried out on cultured cells. This study confirms similar findings of previous work conducted on lung cancer (5).
Until a few years ago both selenium that vitamin E were widely used by patients for the prevention and treatment of prostate cancer, but in 2009 is published in JAMA a population study on a large scale to evaluate the effect of these compounds on tumor prevention (4).
They are recruited and randomly assigned 35,533 healthy individuals in North America and divided into four treatment groups: intake of selenium and Vitamin E in combination, intake of selenium and vitamin E alone, placebo.
In the follow-up of 7 years that followed the risk of prostate cancer in patients undergoing to supplementation with vitamin E alone had increased by 17%, also it was not possible to show any benefit among patients treated with selenium alone or in combination with Vitamin E.
Another large multicenter study, following the previous year, compared the intake of selenium versus placebo in men with high grade prostate cancer. Selenium supplementation did not show any benefit in the treatment group (4).
Unfortunately, for substances that later will review there are no clinical studies of the level of those exposed above and must be limited to the analysis of experimental tests carried out on animals or cell cultures which give us the “signs” and “suggestions” for their use in human beings.
Turmeric and prostate cancer
Curcumin is one of the main components of turmeric, a spice carefully designed for its proven anti-inflammatory and anti-tumor activity.
Like many other natural substances has the ability to act on a wide range of molecular targets at the cellular level: transcription factors, growth regulators, adhesion molecules, apoptotic genes, regulators of angiogenesis and cell signaling molecules, specialized topics that surpass a layman’s discussion like this.
In hormone-refractory prostate cancer, it was found that curcumin in addition to conventional treatment can decrease the proliferation of hormone-resistant cells, and enhance the activity and cytotoxicity of the taxanes (conventional chemotherapy) by reducing the resistance of cancer cells in the prostate these chemotherapeutic (14).
Furthermore curcumin could sensitize prostate cancer cells and make them more vulnerable to radiation therapy. Often radiation increase the expression of TNFa which in turn increases the concentration of the NF-kB which induces resistance in the cells to radiation making the resistant tumor with this therapeutic technique. The curcumin in combination with radiotherapy has caused a significant inhibition of TNFa with consequent important and induction of programmed cell death (apoptosis) of the cancer cells (15).
The increased activity of NF-kB promotes tumor cell proliferation, suppresses apoptosis (cell suicide) active angiogenesis (the formation of new blood vessels to feed the tumor) and facilitates the formation of metastases. In some circumstances, the activation of NF-kB can also change the local metabolism and inhibit the immune system to promote the growth of the tumor. The suppression of NF-kB in cancer cells usually leads to tumor regression and this makes NF-kB a promising therapeutic target (58).
Chronic inflammation promotes carcinogenesis of the prostate gland and a high level of PSA (prostate specific antigen) reflects inflammation in place. Curcumin and soy isoflavones have antioxidant properties and anti-inflammatory.
In a study published in “Prostate” in 2010, it was conducted a clinical trial of patients who did not have prostate cancer acclaimed but had a high PSA value index of an inflammatory process in place.
They were administered with soy isoflavones and curcumin to assess the effect on the serum levels of PSA. In patients receiving the combination of PSA levels were also markedly reduced, remarkable fact, the expression of the receptor for the male sex hormones (androgens) was virtually abolished, the latter phenomenon was attributable to the action of curcumin (16).
At the moment there are no clinical studies on the action of turmeric on prostate cancer, but given its high anti-inflammatory and anti-androgenic potential is certainly to be used for supportive therapy in combination with other nutraceuticals including epigallocatechin-gallate.
Soy isoflavones include genistein, daidzein and glycitein. Among these, genistein has been the subject of numerous studies for the inhibition of prostate cancer.
In 1998 he was published in the prestigious “Journal of the National Cancer Institute,” a study that correlated the nutritional and socio-economic factors with mortality from prostate cancer. In fact, as far as this cancer there are large international variations in both the incidence rate in both mortality and these data have always been attributed to environmental and nutritional factors have a strong influence on the development of the disease (24).
– The study showed that the mortality rate for prostate cancer is increased by the intake of animal fats but vegetable fats.
– The fish seems to be protective for the possibly cancer for the intervention of the omega-3 fatty acids that inhibit growth of the tumor is prostate than in other organs.
– The lowest mortality rates are in the Far East (Japan and Hong Kong) (17). This has been linked with the fact that Asians have the highest per capita consumption of soy products, consumed as tofu, soy milk.
Also other previous studies have shown that an increase of tofu consumption was associated with a reduced risk of prostate cancer (18-19).
– The consumption of milk is positively and strongly associated with mortality from prostate cancer (57), a result consistent with other studies that have found that a high consumption of milk and other dairy products correlated with an increased risk of prostate cancer ( 20-21).
La Vecchia et al. have shown that taking two or more servings of milk per day lead to a significantly increased risk (22), which is not achieved by the intake of high-fat dairy products like cheese and butter.
Another study of the Roswell Park Memorial Institute (23) found a strong association between consumption of whole milk and prostate cancer, but not with skimmed milk supporting the hypothesis that the incidence of prostate cancer is linked to the assumption of fat animals.
Genistenin is the predominant isoflavones in human nutrition, contained mainly in soybeans but also in other legumes such as peas, beans and lentils. From epidemiological studies it was found an inverse association between soy intake and risk of developing prostate cancer.
It has important health properties: lowers the incidence of cardiovascular diseases, prevent osteoporosis, reduces the neuro-vegetative of post-menopausal disorders, it helps reduce body mass and adipose tissue. It has also excellent tumor prevention properties, in fact, in vitro studies has been shown to be capable of inhibiting the growth of prostate cancer cells both androgen-dependent both androgen-independent.
Genistein plays an interesting anti-tumor effect and increasing the anti-cancer activity of certain chemotherapy drugs. More in particular it has been shown that genistein has greatly enhanced the apoptosis triggered by docetaxel (chemotherapy important) in prostate cancer cells (25). Also in a paper published in “Cancer Metastasis Revue” 2014, some researchers have shown that genistein may increase the effectiveness of radiation therapy through the inactivation of NF-kB, a very important substance whose aberrant activation often is observed in many tumor forms ( 26-27).
These results suggest that isoflavone could become a promising nutraceutical for the treatment of tumoral forms in combination with classical therapies.
It was also studied the potential anti-metastatic genistein with a paper published in “Cancer Reaserch” in 2008, conducted on animal models and in which it is seen that the substance inhibits the early stages of the metastatic cascade such detachment and cell invasiveness, significantly increases cell adhesion blocking its motility. In this study genistein decreased metastasis by 96% and induced changes in morphology indicative of greater adherence cell nucleus but, unfortunately, did not alter in a significant cell growth (28). However it is demonstrated for the first time that appropriate concentrations of genistein in the diet are able to inhibit metastasis of prostate cancer cells.
A clinical study published in “Prostate” in 2004, was carried out to determine the effectiveness of isoflavones in patients with prostate cancer at an early stage and increased levels of PSA (prostate specific antigen prostate cancer marker) (29).
The results showed that the serum concentration of free testosterone (male hormone implicated in tumor development) and PSA were reduced in the isoflavone group compared to placebo. 19% of patients in the group treated with isoflavones has seen a reduction in the total PSA of more than two points suggesting that the substance may decrease the production of testosterone, which in turn would reduce the expression of PSA (29).
It was also performed a clinical study of patients with prostate cancer who also had consensual rising PSA “Nutrition Cancer” 2003. The study consisted in the administration of 100 mg twice daily isoflavone soy for a period from 3 to a maximum of 6 months.
There have not been sustained declines in PSA but its stabilization was achieved in 83% of hormone-sensitive patients and in 35% of hormone-refractory.
In addition there was a decrease in the growth rate of serum PSA in hormone-sensitive group, a decrease from 14 to 6%, whereas in hormone-refractory group there was a decrease from 31 to 9%. The conclusion was that supplementation with isoflavones may be helpful for a high percentage of patients (30).
Lycopene Lycopene is a powerful antioxidant substance belonging to the family of carotenoids, organic pigments that are found in plants and are particularly abundant in tomatoes.
Interest in anti-cancer properties of lycopene have a sound scientific basis and considerable epidemiological studies from around the world. The lycopene to the 9-21 mg dose per day, unlike other types of fruits and vegetables, has a predilection for reducing the risk of prostate cancer. In a study of 50,000 men, 812 developed prostate cancer and between dietary variables only lycopene was associated with a reduction in prostate cancer risk of 21% (31).
Its antioxidant and anti-inflammatory effects are manifested by regulating the activation of NF-kB nuclear factor, transcription key element of the inflammatory process often expressed in solid tumors (32). Its presence is associated with worse survival in most of the tumors and lycopene, as other natural substances, going to reduce the concentration of this factor decreases the risk and increases the overall survival.
Modulates signaling pathways that control cell growth and programmed cell death (apoptosis).
It ‘was proven that lycopene potentiates the anti-tumor activity of docetaxel (the only traditional chemotherapy that has proven benefits in terms of survival) in prostate cancer both in vitro and in vivo (33). In an animal study with docetaxel in combination with lycopene it resulted in an increase in the regression of the tumor by 38% compared to treatment with docetaxel alone (33).
also clinical trials were performed to test the effects of lycopene in cancer patients.
In a study published in “Clinical Medicine Urology” in 2008, the administration of 30-45 mg / day of lycopene in patients awaiting prostatectomy, had increased the plasma level of ‘isoflavone and had decreased the concentration of free testosterone suggesting that the substance he could suppress the expression of prostate specific antigen (PSA) (34).
Another clinical study showed that the plasma PSA level was decreased by 18% in the group treated with lycopene, while it was increased by 14% in the control group (35) suggesting that it could be a promising treatment in prostate cancer therapy.
E ‘it was also carried out a study with a combination of lycopene and soy protein in patients with recurrent prostate cancer and rising PSA (36). This association has been shown to have a significant inhibitory effect on both the PSA on both VEGF (vascular endothelial growth factor). This substance is produced by cancer cells from the first moments of their training and need to meet their increased metabolic demands and also contributes strongly to the new formation of new blood vessels suitable for the propagation of the tumor. The association between lycopene and soy is promising and deserves further study through additional clinical studies.
At present it seems that the optimal dosage to induce a natural chemo prevention and a discrete anti-tumor activities of both 0.5 mg per kg, in other words in a 80 kg man should be administered 40 mg of Lycopene day distributed in twice daily.
Cruciferous Indol-3-carbinol and Dim
Cruciferous Cruciferous vegetables are a large family of herbaceous plants whose main components are the cauliflower, the Roman broccoli, cabbage, turnips and radishes. The phytocomplexes of this botanical family are carefully designed because the epidemiological evidence has amply demonstrated that intake of these vegetables leads to a reduced risk of cancer among them that prostate (37-38). Among the various metabolic products sulforaphane and indole-3-carbinol have been shown to inhibit the blocking prostate cancer is the ‘initiation is the progression in vivo and in vitro. They have been widely studied for their properties to prevent, inhibit and reverse the progression of cancer.
Cato the Elder (234-149 B.C.) in his medical treatise he wrote: “If an ulcer appears cancerous breasts, apply a crushed cabbage leaf that will do very well.” modern research after 2000 years has fully confirmed the earlier observations.
Indole-3-carbinol is an important metabolic product of cruciferous and exerts powerful proven antitumor effects both in animal cell lines (39-40-41) and human cell lines (42-43), and has received much attention as possible natural chemo preventive agent (44).
Another very important compound derived from Indole-3-carbinol is 3.3 diindolylmetano (DIM) that forms during cooking (49) and in the environment of the stomach acid; It has proven to be a powerful anti-cancer agent by numerous studies carried out both in vivo and in vitro. Markedly inhibits the growth of human prostate cancer cells, breast, colon, and cervix. These effects are mediated by signaling pathways of numerous block in neoplastic cells that lead to impairment of cell proliferation and severely limit the invasiveness and migration, namely the statisation destination, also stimulate the death of cells by apoptosis (cell suicide ).
At present there are many ongoing clinical studies that testify to the great scientific interest that revolves around the cruciferous compounds.
The studies which have focused more research efforts concerning prostate cancer and the uterine cervix.
In an article published in “Cancer Metastasis Revue” in 2014, the researchers found that I3C and DIM given in combination with chemotherapy more effectively reduce the proliferation of prostate cancer compared to only treatment with classical chemotherapy (50).
I3C it was found that increases the anti-cancer efficacy of cis-platinum (powerful and utilizzatissimo traditional chemotherapy) in prostate tumor cells (51).
The 3.3-diindolylmethano (DIM) has been the subject of chemical modifications with the intent to produce a compound even more bioactive than natural, it generated the BioResponse 3.3-diindolylmethano (BR-DIM) that owns more activity therapeutic.
In a study published in “American Journal of Traslational Research” in 2010, the recommended dose was 225 mg twice daily.
A patient with such administration has suffered a decrease in PSA by more than 50%, another patient obtained stabilization of the PSA and ten others had an initial slowdown in increasing concentration of such prostatic markers (52-53).
SCHEMA THERAPY AND DOSAGE indole-3-carbinol
Indole-3C is now available in pharmacies specializing in dosage form and assumptions consist cps at doses ranging from 200 to 300 mg. Typically you use this mode of administration:
I3C cps 300 mg 1 after breakfast
I3C cps 300 mg 1 after dinner Associations with other natural substances can be manifold, but the most used are with epigallocatechin gallate (green tea) and turmeric.
Turmeric over other compounds performs an intense anti-inflammatory as well as anticancer, and prepares the ground for the action of other products.
A classic administration schedule two substances includes:
Morning after breakfast:
1 cps 300 mg I3C
1 cps Meriva Turmeric 500 mg
Night after dinner::
1 cps 300 mg I3C
1 cps Meriva Turmeric 500 mg
Therapy scheme with three substances includes:
Morning after breakfast:
1 cps 300 mg I3C
1 cps Meriva Turmeric 500 mg
1 cps EGCG (green tea) 400 mg
1 cps EGCG (green tea) 400 mg
1 cps 300 mg I3C
1 cps Meriva Turmeric 500 mg
1 cps EGCG (green tea) 400 mg
In a complex and difficult study of molecular biology published in “PLoS ONE” 2012, it is demonstrated that DIM is able to inhibit the growth of cancer cells by increasing the expression of a protein family (let-7), which in turn lower the concentration of a closely related protein (EZH2) with the gene clonus activity and aggressiveness of the tumor (54).
In simple words DMI manages to raise the “good” proteins that keep at bay those “bad” that otherwise would allow cell growth. The importance of the study derives from the fact that it has been proven as a natural substance and free of toxicity can edit complex biomolecular structures which an entire family of proteins, the power supply as anticancer therapy in other words there!
Dott. Claudio Sandri
Translated by Ms Jeanne Marie Arcaini
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