Keywords. Prostate cancer, Cellular cycle, P53 apoptosis, molecular markers, survivin, BcL2, Bax, Hypoxia, fermented soya extract, curcumin, liquid Cartilage Extract, green propolis, pomegranate.

Some of the images are not coming through in WORD, I hope you can find them in the emails.

The Molecular Basis of Prostate Cancer and Targeting Therapies

Prof. Serge Jurasunas

This article was reviewed by Dr. Joseph Brenner, medical oncologist head of the Oncology Institute, Wolfson Hospital, and director of the New-Hope Medical Center for Integrative Cancer Treatment in Holon, Israel. Dr. Brenner was trained in chemotherapy and radiotherapy at the Memorial Sloan Kettering Medical Center in New York City.

Abstract in shading or box??

Abstract

Cancer, namely prostate cancer is a disease of the cell cycle regulation and checkpoint causing uncontrolled cellular proliferation, tumor promotion, apoptotic failure, angiogenesis, tumor growth and metastases invasion.

The P53 tumor suppressor gene is the central hub in the cellular growth pathway; but other genes transcriptionally controlled by P53 and other transcription factors are mostly involved in prostate cancer including Myc, Pten, TGFB, BcL2, and especially survivin, an inhibitor of apoptosis. Survivin is highly expressed in prostate cancer with a metastasis condition and is associated with poor patient prognosis and resistance to chemotherapy. Up-regulated BcL2, survivin, and failure or P53 mutation are also associated with metastasis invasion and disease progression.

Restoring P53 function and targeting apoptotic and anti-apoptotic players together with the activation of immune cells as the natural killer cells (NK cells) is now emerging as a novel anticancer therapy. The clinical application of blood testing for apoptotic and anti-apoptotic genes remains an important goal from the perspective of establishing a personal therapy for each patient.

Many lines of study have suggested that some natural products may have the ability to target a cell’s signaling pathway, downregulate BcL2 and survivin, upregulate the Bax gene, and restore P53 function. Tegaran (Zhen Hua), a compound made from unmodified fermented soya extract that contains isoflavones, protease inhibitors, saponins, phytic acid, and genistein, has shown therapeutic capacity for adjuvant treatment of solid tumors. Zhen Hua is a most effective agent that targets transcription factors, decreases NF-KB activity, VEGF, and MDR1. It also targets BcL2, Bax, and MDR1 expression in various cancer cell lines.

Curcumin, the second compound, is a yellow coloring ingredient derived from Curcuma longa L.; it is one of the most extensively investigated and well-defined chemopreventive agents. A large variety of pharmacological properties, including anti-inflammatory, antioxidant, and anti-cancer, have been demonstrated in preclinical animal and pilot human studies. Curcumin arrests the cell cycle at GO/G1 or G2 (same as most chemotherapy) inducing apoptosis. Curcumin is known to target most of the hallmarks of cancer, downregulate BcL2, survivin, VEGF, Cox2, and NF-kB and increase immune cell activity.

The third compound is a liquid cartilage extract (LCE) having properties that target most of the angiogenesis mechanisms including VEGF and MMPs. Several studies reveal that LCE interferes with VEGF binding and signaling while inhibiting MM 2, 9, and12, which are often overexpressed in tumors and involved in both migration of endothelial cells and tumor invasion. Other secondary but interesting dietary compounds like green or black propolis and pomegranate also have shown some interesting ability as a support in the protocol of prostate cancer.

Introduction

In North America, prostate cancer is the most commonly diagnosed cancer in men; before, it used to be lung cancer. In 2012, 177,489 men were diagnosed with prostate cancer in United States and 27,244 men died from prostate cancer (US cancer statistics working group 1999-2012 – CDC and NCI, 2015). In 2012, 1.1 million men were diagnosed with prostate cancer. A larger increase of prostate cancer is expected by 2020 (CDC), not only in United States but in most industrial countries. Prostate cancer is the cause of death in 15% of patients diagnosed with the disease in the USA but in 50% of those diagnosed in England. The difference is most probably due to huge screening efforts in the USA by PSA detection in healthy individuals and early detection of the disease due to screening (2011 Meeting of United Kingdom Association of Cancer Registries and National Cancer Intelligence Network (NCIN). Abstract 86. Presented June 16, 2011).

Most prostate cancers are asymptomatic and slow growing; however, a third of the cases are more aggressive and fast developing.¹ Prostate metastasis spreads relatively quickly to other parts of the body, particularly lymph nodes, rectum, bones, and brain, ultimately leading to death. Treatment includes a combination of surgery, hormonotherapy, radiation therapy, and chemotherapy that may be effective for the cure of localized disease; but there is no effective treatment strategy for metastasis, thus prostate cancer remains painful and often incurable.² Aggressive prostate cancer accounts for more cancer-related mortality than any other cancer including lung cancer. Despite advances in local treatment, approximately 25% of radically treated patients will develop disease progression³; and in 10-20% of present cases, starting at the primary diagnosis of bone metastases, the use of hormones and or chemotherapeutic drugs could only extend the lives of these men or those with other advanced cancer by months or a few years at best. Prostate cancer tumor progression and aggression can be secondary to genetic and epigenetic changes⁴ through the activation of oncogenes and inactivation of tumor suppressor genes, to an angiogenic switch⁵ and immune evasion.⁶

Recent advances into the molecular function of pro-apoptotic genes and inhibitors of apoptosis open a new door to potential therapeutic targeting opportunities for the treatment of prostate cancer, while prevention and diagnostics at an early stage remains a main goal in naturopathic oncology.⁷

Prostate Cancer

Evidence indicates that chronic inflammation promoted by oxidative stress and dietary factors⁸ damages the DNA genome along with mitochondrial DNA (mtDNA). Several reports have highlighted the link between metabolic alteration and mtDNA mutation in prostate cancer and associated these factors to the development and progression of the disease.⁹ The progressive loss of cell cycle regulation, causing uncontrolled cellular proliferation, is today attracting more attention to the point where we say that cancer is a disease of the cell cycle.¹⁰

According to an article published in Lancet (August 2004), “Gene Therapy for Prostate Cancer,” selective killing of prostate cancer can be achieved by the manipulation of cell-cycle control and apoptosis through tumor suppressor genes, such P53 and BAX. (See my conference presentation, “How to understand and treat cancer from a molecular basis” at http://www.slideshare.net/SheldonStein/how-to-understand-treat-cancer-w-molecular-markers.)

Evasion from apoptosis is critical for tumor growth and a main hallmark in cancer.¹¹ Abnormal cells accumulate mutations, become resistant, and start to proliferate. Metastatic cancer cells can escape from the primary tumor through the loss of cell-adhesion, induction of cell mobility, and start to invade the surrounding tissue. They enter into blood or lymphatic circulation, travel to distant organs and establish a new tumor that can keep dormant over several years¹² or reactivate after a few months inducing angiogenesis to grow again.

In fact, there are several primary contributors in the emergence of androgen-independent metastatic prostate cancer such as activation of survival pathways, including apoptosis, suppression of anoikis resistance,¹³ and increased neovascularization. Of course, evasion from immune surveillance is also a contributor.

Therefore, as I will show in this article, targeting apoptotic players and angiogenesis is of vital therapeutic significance since resistance to apoptosis plays a key role in therapeutic failure to standard treatment strategies and plays a paramount role in tumor progression and disease recurrence.^14,15

Several basic elements are involved in the malignant process and are considered hallmarks of cancer:

• Evading apoptosis (P53 tumor suppressor),

• Overexpressed BCL2 gene,

• Activated P13K/AKT pathway,

• Loss of E. Cadherin,

• Overexpressed Survivin gene, and

• Sustained angiogenesis.

Without these hallmarks, there would not be any cancer, a very complex disease. We have a new promising avenue that leads to new diagnostics and more effective treatments for cancer.

Molecular Basis of Prostate Cancer

Although there is a myriad of genes implicated in cancer, we are going to discuss briefly some of the most important ones associated with prostate cancer. Somatic genetic and epigenetic alteration occur in prostate cancer such the loss of the tumor suppressor P53 network, PTEN, C-Myc, apoptosis, invasion, angiogenesis and metastases. P53 tumor suppressor is situated at the crossroad of a network of signaling pathway¹⁶ composed of subway stations where each gene is connected with each other and engage in cross talk. P53 is a central hub in the cellular growth pathway and cooperates with other genes and transcription factors, including Myc, PTEN, NF-kappaB, FG, and TGFB .

C-Myc is one of the most commonly studied oncogenes, being a regulator gene that is coded for transcription factors associated with growth control, cell cycle, differentiation and apoptosis.¹⁷ C-Myc is frequently amplified in prostate cancer patients. FISH analysis identified overexpression of C-Myc in 9% of primary tumors but 75% in advanced cancer patients.^18,19 There is cross talk between C-Myc and P53; C-Myc increases P53 activity in the case of apoptosis, and P53 mediates C-Myc activity but not in the case of mutant P53.^20,21

PTEN is another tumor suppressor frequently inactive in prostate cancer,^22,23 one of the most common genetic alterations in prostate cancer. Loss of PTEN is needed for cancer progression to occur in prostate cancer²⁴ and a common event in treatment. Resistant and poorly differentiated prostate cancer leads to constitutive activation of the P13/AKT, a regulator of cell cycle and directly related to cellular proliferation and cancer, including prostate cancer.²⁵ Both PTEN inactivation and P13/AKT hyperactivity are hallmarks of aggressive prostate cancer, resistant to chemotherapy.²⁶ There is cross talk between PTEN and P53 tumor suppressor; P53 can regulate PTEN at the transcription level, and PTEN can regulate P53 protein level activity²⁷ or can be regularized by MDM2 (a negative regulator of tumor suppressor P53). Therefore, PTEN also sensitizes cells to chemotherapy²⁸ by increasing apoptosis.

P53 mutation downregulates C-Myc and other transcription genes associated with apoptosis, angiogenesis and immune system such as the transforming growth factor beta (TGFB),²⁹ an essential regulator of cellular physiologic processes including proliferation, differentiation, cell survival, apoptosis, angiogenesis, and immune response. TGFB plays a positive role as a tumor suppressor by promoting apoptosis at early stages of the cancer process, facilitated by the presence of WT P53 but not with the presence of mutant P53 that inhibits the TGFB tumor suppressor. Upregulation of TGFB can stimulate invasion, angiogenesis, and metastases.³⁰ Elevated TGFB levels in a patient’s serum provide a significant prognostic value for highly aggressive metastatic diseases and poor patient prognosis in prostate cancer.³¹ For this reason, direct targeting of TGFB receptors also provides a promising therapeutic avenue in the inhibition of tumor progression in clinical applications.³²

Another example is the transcriptional cross talk between the P53 tumor suppressor and the nuclear factor kappa B (NFKB), a major mediator of inflammation and suspected to be involved in cancer development, progression, and activation in prostate cancer.³³ NFKB is associated with angiogenesis, activating VEGF, the protease enzymes MMP-9, apoptosis, and immunosuppression. Considering the deregulation of NFKB and P53 pathways in numerous cancers, it is not surprising that an extensive cross talk between both pathways exists at various levels.³⁴ Normal P53 can suppress the activity of NFKB³⁵; but mutant P53, to the contrary, enhances NFKB, constitutively activated in human prostate adenocarcinoma. This correlates with resistance to various chemotherapeutic agents, such as paclitaxel, in prostate cancer and disease progression. Targeting NF-kappa B in association with chemotherapy strongly enhances the apoptotic potential of the chemotherapy and is associated with suppression of angiogenesis and metastases in human prostate cancer.³⁶

This is why, in addition to the loss of tumor suppressive functions, mutant P53 increases oncogenic function, contributing to carcinogenesis, tumor progression, invasion, metastases, and drug resistance.³⁷ Reversing P53 mutation to normal, wild-type function is associated with increasing apoptosis and decreasing tumor progression.³⁸ I have demonstrated over the past years how some selected dietary agents and bioactive compounds can reverse mutant P53 to a normal WT-P53 tumor suppressor gene in numerous cancers and increase the destruction of cancer cells.^39,40 (For more references read: Oncogenic activation in prostate cancer progression and metastases: Molecular Insight and Future Challenge. Journal of Carcinogenesis. (April 17, 2012) available online.)

Anti-Apoptotic Players in Prostate Cancer

BCL-2 plays a key role in earlier cancer development. BCL-2 is the founding member of the BCL-2 family of regulator proteins that regulate cell death (apoptosis) via the mitochondria by either inducing apoptosis (BAX gene) or inhibiting apoptosis (BCL-2).⁴¹ BCL-2 is considered an important anti-apoptotic gene and protein that blocks programmed cell death.⁴² BAX is the homologue of BCL-2, a pro-apoptotic protein that resides in the cytosol. Under stimuli, BAX is transcriptionally active by P53, leading to its subsequent insertion into the outside membrane forming mitochondrial pores⁴³ and increasing its permeability,⁴⁴ which leads to the release of apoptotic factors such as cytochrome C that activate the apoptotic cascade.^45,46

BCL-2 is located in the inner membrane of mitochondria and, when overexpressed, blocks the apoptotic protein BAX, preventing the formation of mitochondrial pores inhibiting the release of the enzyme cytochrome C, thus either inhibiting or reducing the death of cells.⁴⁷ Both in-vitro and in-vivo studies have established that BCL-2 and other anti-apoptotic members of its family are significantly upregulated for the progression of prostate cancer and in aggressive prostate cancer phenotypes.⁴⁸ Overexpressed BCL-2 in human prostate cancer confers resistance and prolongs cell survival, increasing progression of metastases despite chemotherapy or exposure to radiation therapy.⁴⁹ According to an article published in Lancet magazine about prostate cancer and radiotherapy (June 2007;8:475-478), conventional radical external-beam radiotherapy is limited to a dose of 64-70 Gy in 1.8-2.0 Gy fractions because of the risk of long-term toxic effects to the bladder and rectum. However, within five years of being treated with this type of radiotherapy, up to 33% of patients will relapse, which seems unacceptable.

Some studies that include a large patient population demonstrated that BCL-2 expression levels were of major significance in predicting clinical outcome after brachytherapy of prostate cancer patients. BCL-2 was significantly higher in prostatic tumors resistant to radiotherapy compared with radiation responders. Recent studies have linked the expression of BCL-2 to the development of the hormone resistant phenotypes of advanced prostate cancer.⁴⁹ BCL-2 is negatively regulated by P53 to trigger apoptosis.⁵⁰ The response to cancer cells to exposure of radiotherapy is not only associated with BCL-2 expression but P53 tumor suppressor.⁵¹ Therefore, we understand that loss of P53 function may negatively influence the expression of BCL-2 in prostate cancer.⁵²

The BCL-2/BAX ratio is considered a predictive marker for the response to chemotherapy or radiation therapy in prostate cancer.⁵³ Where other oncogenes are activated, BAX is lost with a poor ratio. BCL-2 overexpression may confer an additional growth advantage to tumor.

Prostate cancer can become resistant to apoptosis during the progression of the disease and metastasis via multiple molecular mechanisms. BCL-2 is not highly expressed in early local prostate cancer but is highly expressed in metastatic tumors. It can be triggered in several ways such as inflammation and by NFKB, which, in fact, transcriptionally regulates BCL-2.⁵⁴

As discussed previously, C-Myc is frequently amplified in prostate cancer; and there is cross talk or intervention between C-Myc and BCL-2⁵⁵ that increases expression. Often, this is the result of excessive chemotherapy.

Overall, BCL-2 overexpression is associated with progression of prostate cancer, tumor resistance to chemotherapy/radiation, and a poor prognosis. As a result, it may prove to be an important independent or adjuvant predictor of resistance to apoptosis during conventional treatment and needs to be targeted.

The Role of Survivin in Prostate Cancer

Survivin is a new anti-apoptotic protein with bifunctional function implicated in the protection of apoptosis and modulation of cell division,⁵⁶ playing a crucial role in cancer development and metastatic potential. Survivin is a strong inhibitor of apoptosis protein,⁵⁷ strongly expressed in embryonic and fetal organs but undetectable in differentiated normal tissue. It is upregulated in 84% of all cancers including breast, colon, bladder, pancreas, lymphoma, and prostate.⁵⁸

Therefore, survivin becomes a new cancer biomarker and an attractive molecule for early detection and prognosis of cancers such as breast, prostate, bladder, and colorectal cancer.^59,60

The primary function of survivin is the inhibition of apoptosis under stimuli, but it also regulates mitosis, which is associated with cell cycle and carcinogenesis.^61,62 Survivin in the mitochondrial membrane is rapidly released in the cytosol in response to apoptosis and inhibits apoptosis either directly or indirectly by interfering with the function of caspase 3, caspase 7, and caspase 9.⁶³ A family of 14 cysteine proteases required for the initiation and execution of apoptosis may also be a caspase-independent way by interaction and cooperation with Hepatitis B interacting protein (HB x IP) or XIAP to inhibit apoptosis.⁶⁴ Survivin expression enhances the metastatic potential of the tumor, using HBxIP and XIAP and even NF-kappa B as co-factors, and increases the resistance of cancer cells.

The expression of survivin increases gradually from normal prostate tissue, to primary low-grade prostate carcinoma, with the highest expression observed in the foci of prostate cancer metastasized to the lymph nodes.^65,66 This pattern of gene expression suggests that survivin is associated with disease progression and accelerated rate of recurrence⁶⁷ and increased resistance to therapy.^68,69 Therefore, it makes survivin an attractive target for prostate cancer therapeutics or prevention of recurrence, as I am going to show with examples of clinical cases.

Survivin gene expression is transcriptionally regulated by wild type P53.⁷⁰ The loss of P53 function not only deregulates survivin gene expression but also BCL-2 gene expression with a stronger anti-apoptotic mechanism. Although they differ,⁷¹ both confer a more resistant type of cancer cells and a bad prognostic.⁷²

Hypoxia and Survivin Expression

Hypoxia increases survivin expression and promotes angiogenesis, proliferation, and metastatic invasion. Hypoxia is a potential prognostic and predictive factor in prostate cancer (and other cancers) that significantly correlates with the Gleason Score⁷³ and leads to the selection of aggressive cancer, decreased sensitivity to apoptosis, and an increased clinical stage.⁷⁴ Hypoxia may have a negative effect by increasing angiogenic potential and metastatic capability leading to tumor expansion and metastatic progression, such as in advanced stage prostate cancer.⁷⁵

The presence of hypoxic regions in a solid tumor is a common phenomenon and results in dramatic alteration in gene expression⁷⁶ that increases the level approximately threefold,⁷⁷ which in turn increases the resistance and aggressiveness of prostate cancer cells. Upregulated survivin^78-80 was shown to favor angiogenesis, increasing vesicular endothelium growth factor (VEGF) and fibroblast growth factor (FGF), also identified in prostate cancer.^81-83

Survivin is also strongly upregulated in angiogenically stimulated endothelium in-vitro and in-vivo and protects endothelial cells from apoptosis, not only during the proliferative phase of angiogenesis⁸⁴ but also during the remodeling phase mediated by angioprotein.

Vesicular endothelium growth factor is a potent stimulator of angiogenesis that tumors need to expand. Cancer cells can express VEGF to metastasize, which also correlates with P53 mutation in hypoxic tissue.⁸⁵

Highly expressed survivin in prostate cancer induces resistance to treatment⁸⁶ and is associated with aggressive prostate carcinoma.⁸⁷ A new avenue is emerging to increase the effectiveness of anticancer agents by targeting survivin at the clinical level.^88,89 On the other hand, survivin expression usually is correlated with the BCL-2 expression and often the loss of P53 that strongly increases the resistance of cancer cells. It may serve as a good predictive factor to determine the response to chemotherapy and radiotherapy with cancer patients and reduce the risk of metastases diffusion by targeting P53, BCL-2, and survivin.⁹⁰

Evidence has shown that restoring P53 function not only results in increasing apoptosis in prostate cancer⁹¹ but downregulates BCL-2 and survivin gene expression, increasing the effectiveness of chemo/radiation therapy. Targeting apoptosis in prostate cancer is now emerging as a novel anticancer therapy.⁹²

In summary, key points regarding survivin overexpression are as follows:

• Absent in normal tissue, highly expressed in cancer tissue;

• Can be used as a biomarker;

• Released by mitochondria under pro-apoptotic stimuli;

• Inhibits caspases 3-7-9;

• Enhances angiogenesis;

• Is associated with chemotherapy resistance and increased rate of tumor recurrence;

• Indicates poor outcome; and

• Predicts prostate cancer recurrence.

The Protocol for Prostate Cancer

New avenues in the apoptosis pathway, modulation of inflammatory mediators, oncogene expression, and the immune system offer excellent opportunities for approaching the disease of cancer differently. These new approaches can render antineoplasic agents more efficient, avoid unnecessary treatments and their side effects, and prevent the progression of the tumor to advanced metastases disease.

It makes an overwhelming difference when you do blood testing of your patient because you realize that patients with the same cancer have different results concerning the activity of tumor suppressors and oncogenes and different ratios between the pro-apoptotic and anti-apoptotic proteins, which permit you to make your prognostic. Another test we use is the Tumor Marker-2 – Pyruvate Kinase that indicates the metabolic activity of the tumor and supports the antigen PSA test. With these tests, you can follow the recovery of patients. Each patient needs a personalized or individualized treatment based on the results of the blood tests, not to mention the age, the general status, and family background.

My protocol for the treatment of prostate cancer has been developed and refined over many years of practice and observation. As a cornerstone, we use plant-derived dietary agents and other ingredients that are immunomodulatory with multi-targeting properties against cancer. These agents are safe, increasing chemotherapy/radiation effectiveness while reducing unpleasant side effects. Also, this approach has proven efficiency in treatment without conventional therapy.

The Effects of Soy Extract on Various Cell Lines

Tegaran is one of the most effective anticancer agents adapted to various types of cancers including prostate cancer. Tegaran is made from fermented soy that contains phytic acid, protease inhibitors, saponins, phytosterols, and genistein. All in-vitro and in-vivo tests and clinical studies have confirmed the positive effects of the components in the fermented soy extract as therapeutic approaches for adjuvant treatment of solid tumors. Tegaran targets most of the molecular aspects of cancer that include pro-apoptotic genes, inhibitors of apoptosis, transcription factors, MDR1 expression, and immune cell reduction of cachexia; and it increases health status.

Tegaran fermented soy extract increases the efficiency of chemotherapy. At a low dose, doxorubicin (10 D) combined with a high dose of fermented soy extract (100 D) resulted in significant BCL-2 reduction identical to that obtained with a high dose of doxorubicin (100 D) without fermented soya extract. Also, some studies found that soy isoflavones enhance radiosensitivity, induce G2/M cell cycle arrest, inhibit the DNA repair mechanism, boost BAX gene expression, and inhibit BCL-2 and survivin gene expression (Free Radic Biol Med. 2011;51:289-293.

Tegaran increases the activity of natural killer cells (NK cells) in just hours and significantly raises the leucocyte count (WBCs). We know that cancer patients with low natural killer cell activity are at risk of metastases and/or disease recurrence and shorter survival.^93,94 Manipulation of the immune system has been a long-term goal of many immunotherapeutic approaches to cancer.

Tegaran plays an important role by inhibiting VEGF and MMPs to prevent tumor growth and new microcapillary vessels.⁹⁵ There is a particularly high level of MMP7 and MMP9 associated with prostate cancer compounds that correlate with a higher Gleason’s score.^96,97 Over the past years, we have observed the efficacy and anticancer property of Tegaran with prostate cancer, including advanced stage with high PSA and high Gleason’s scores that returned to normal range. Most cases have shown high levels of survivin expression that were lowered the same as PSA with our protocol.

Tegaran has been subject to considerable numbers of tests and clinical studies that are available at www.tegaran.com. Tegaran is manufactured in Switzerland and has FDA registration.

The next important dietary agent we use is the curcumin because it acts as a blocking agent in the different stages of cancer and inhibits malignant cell proliferation during promotion and progression of prostate cancer.

Curcumin inhibits NF-kappaB, which interferes with signaling mechanisms such as apoptosis and angiogenesis, by activation of the MMP9 which is downregulated by curcumin.⁹⁸ In prostate cancer, curcumin has shown the ability to increase the destruction of cancer cells by halting the G2/M phase of the cell cycle.⁹⁹ Curcumin sensitizes tumor cells to various antineoplastic agents including cisplatin, 5 FU, Taxol, and Taxotere. It also confers radiosensitizing effects in prostate cancer cell line PC 3.¹⁰⁰ Curcumin targets the anti-apoptotic proteins such BCL-2 and surviving, downregulates the P13K/AKT pathway, and increases P53 function, thereby triggering apoptosis and decreasing¹⁰¹ the resistance of cancer cells to chemotherapy/radiation.

Because curcumin is well known to inhibit NF-kappaB upregulation implicated in tumor growth, progression, and drug resistance, curcumin can play a key role in anti-cancer therapy.¹⁰² COX2, regulated by NF-kappaB, is a form of cyclooxygenase that catalyzes the rate-limited step in prostaglandin synthesis from arachidonic acid and plays an important role in prostate cancer.¹⁰³ COX2 is highly expressed in epithelial cells of high-grade prostatic cancer and induces proangiogenic factors such the VEGF¹⁰⁴ and the protease enzyme MM9, upregulated in prostate cancer and involved in the angiogenic process.¹⁰⁵

Curcumin induces apoptosis and inhibits COX2 and MMP9 by inhibiting NF-kappa B.¹⁰⁶

The curcumin utilized in clinical trials, such as at the University of Texas, M.D. Anderson Cancer Center in Houston, is a liposome curcumin,¹⁰⁷ which is better absorbed by the body. We have developed our own formula of liposomal liquid curcumin in 1500 mg sachets with high bioavailability. Our team of pharmacists who specialize in phytotherapy and the researchers at my pharmaceutical laboratory worked in association with the faculty of pharmacy at the University of Lisbon to perform in-vitro tests concerning the bioavailability of this specialized curcumin.

The next product we use for cancer with bone metastases, including breast and prostate cancers, is a liquid cartilage extract (LCE) available in frozen vials. LCE is a concentrated hydrosoluble extract of liquid cartilage that contains biologically active mucopolysaccharides and proteins with strong antiangiogenic properties.^108,109 I wrote several articles about LCE that show cases of bone metastases before and after the treatment with the LCE included in our protocol: for example “A Case in Which a Combination of Natural Compounds Was Effective in Metastatic Breast Cancer” (Townsend Letter, April 2011), showing major decrease of bone metastasis and increased bone density in the legs after taking LCE extract. More technical information on the anti-angiogenic and anti-inflammatory property of this LCE^110,111 is available in one of my lectures on this subject: “Cutting-edge in oncology for every physician: strategic antiangiogenic treatment: shark cartilage and cancer,” 4^th European Congress on Anti-Aging Medicine, October 17-19, 2008, Paris, France.

Other interesting bioactive dietary agents that we use in the treatment of prostate cancer include propolis extra (CAPE or Caffeic acid phenolic ester), which is a member of the polyphenolic compounds. Present in high concentration in medicinal plants and propolis, it demonstrates antitumor, anti-inflammatory, anti-angiogenic, immunomodulatory, and anti-proliferative activities.^112,113 Most of the dietary agents and medicinal plants induce apoptosis and the destruction of cancer cells. Propolis has a similar effect on prostate cancer,¹¹⁴ inducing growth arrest and suppressing the proliferation of human prostate cancer cell lines.¹¹⁵ Several types of propolis are available, such as red and green propolis from Brazil; but we also use the Portuguese propolis, which has shown major anti-cancer properties.^116,117

Portuguese propolis can block specific oncogenic signaling pathways (C-Myc, B-Catenin, Cyclin 1, NF-kappaB) as well as some intermediaries of the P13K/AT pathways, which in turn leads to a decrease in cell proliferation and growth. This can also act by decreasing cancer stem cell populations. Propolis extra enhances the efficacy of chemotherapy in prostate cancer by increasing cytotoxicity, thus increasing cancer cell destruction with less adverse effects.¹¹⁸

Pomegranate juice is also subject of research associated with prostate cancer. Scientists from the University of California identified components in pomegranate juice that help prevent prostate cancer metastases. It also significantly slowed the rate at which PSA level was rising (PSA doubling time).^119,120

Important Food

Diet is of paramount importance to be included in any prostate cancer protocol. A study conducted by Dr. Dean Ornish has shown how a healthy diet alters the expression in genes in a cohort of 93 men (non-smoking) with prostate cancer (PSA 4-10ng/ml) not electing treatment (surgery, radiation, hormone therapy). After three months of the diet, a comparison showed that more than 500 genes had changed, and oncogenes were down-regulated.¹²¹

My presentations about the molecular basis of cancer and the targeting of pro-apoptotic and anti-apoptotic proteins using dietary agents and how to detoxify the body may be viewed at http://www.slideshare.net/SheldonStein/presentations, posted by Shel Stein on my behalf. The presentations include “How to understand and treat cancer from a molecular basis,” “Protocol for the Treatment of Prostate Cancer,” and “Integrative Cancer – New Theories and Advances in Treatment.” Also, you may visit my new blog: https://naturopathiconcology.blogspot.com

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About the Author:

Serge Jurasunas is an internationally well-known practitioner and researcher in complementary oncology and molecular medicine. He is a professor of naturopathic oncology at Pan Am University of Sciences and Natural Medicine, has delivered lectures in over 45 countries including Russia, Asia, and Australia, and was invited to the Congress on Molecular Medicine in Beijing, China, subsequently receiving an invitation to join the advisory board of the Molecular and Cellular Therapies Journal.

Professor Jurasunas specializes in treating all types and grades of cancer in his clinic located in Lisbon, Portugal, having devoted five decades developing innovative therapies and being a pioneer in several approaches to cancer including immunotherapy, stem cell therapy, SJ therapy, live blood analysis and oxidative dried blood testing. His field of interest includes nutrition and iridology.

He spent the past ten years investigating, researching, and putting into clinical application testing of the P53 tumor suppressor gene and reversal of P53 mutation in cancer patients using selective dietary agents. He also works with other molecular markers associated with cancer in follow-up treatments.

He is a frequent Townsend Letter contributor and author of over 150 papers, lectures, and articles translated into 13 languages. His new book, Health and Disease Begin in the Colon, contains full information about these tests and reflects his 50-year professional career.

Please visit my Blog: NaturopathicOncology.blogspot.com

Contact:

www sergejurasunas.com

Email: Sergejurasunas@hotmail.com Tel: 351.912565038