B (NF-κB). (Pan et al.,
2002)Home ׀ Health News ׀ Treatments ׀ Articles ׀ Links ׀ Disclaimer ׀ Forms/Directions
Understanding Prostate Cancer
Compiled by John Connor, L.Ac. from articles and lectures by Donald Yance and other selected sources, Nov. 18, 2009
Table of Contents
Background
Among men, cancers of the prostate, lung and bronchus, and colon and rectum account for about 50% of all newly diagnosed cancers, and prostate cancer alone accounts for about 25% of incident cases. (Zhang et al 2009) Prostate cancer is the most common malignant tumor in male adults in the Western world, which represents a major cause of cancer-related morbidity and mortality. Botanical mixtures are widely used by patients with prostate cancer. (Yo et al 2009)
In the United States alone, 200,000 men are diagnosed with prostate cancer each year and one out of six men will be diagnosed in their lifetime. As many as 30,000 men die from this disease each year in the US, making prostate cancer the second biggest cancer killer of men, behind lung cancer. (Shah MR et al 2009)
Targeted Therapies Approach to Cancer
Conventional chemotherapy, although directed toward certain macromolecules or enzymes, typically does not discriminate effectively between rapidly dividing normal cells (e.g., bone marrow and gastrointestinal tract) and tumor cells, thus leading to several toxic side effects. Tumor responses from cytotoxic chemotherapy are usually partial, brief, and unpredictable. In contrast, targeted therapies interfere with molecular targets that have a role in tumor growth or progression. These targets are usually located in tumor cells, although some like the antiangiogenic agents may target other cells such as endothelial cells. Thus, targeted therapies have a high specificity toward tumor cells, providing a broader therapeutic window with less toxicity. They are also often useful in combination with cytotoxic chemotherapy or radiation to produce additive or synergistic anticancer activity because their toxicity profiles often do not overlap with traditional cytotoxic chemotherapy. Thus, targeted therapies represent a new and promising approach to cancer therapy, one that is already leading to beneficial clinical effects. There are multiple types of targeted therapies available, including monoclonal antibodies, inhibitors of tyrosine kinases, and antisense inhibitors of growth factor receptors. (Arora and Scholar, 2005)
Donald Yance feels that the emerging concept and practice of targeted therapy flows from the fact that many tumor mutations and polymorphisms provide specific targets for a new generation of drugs that are genetically engineered to uniquely attack, antagonize or inhibit such factors. However, the promise of targeted therapy has yet to be realized: the modern targeted drugs are few, prohibitively expensive, offering minimal benefits in survival, and have many, often serious, adverse effects.
Donald Yance’s approach as outlined in his Eclectic Triphasic Medical System (ETMS) is aimed at the root source of ill-health, with the primary focus being to bring about harmony and balance throughout the body, together with target-specific, non-toxic, or low-toxicity cancer-suppressing agents. This is achieved through the application of synergistic multi-targeting herbal and nutritional formulations, dietary therapeutics, and specific cancer-targeting therapies as indicated. While targeted chemotherapy may also be needed, low doses and metronomic administration are often more effective than “standard of care” guidelines. When approaching a disease such as cancer, it is important to formulate a balanced protocol that addresses both the characteristics of the disease (tumor) as well as the energetic weaknesses of the individual (host). It is when the energy of cancer overrides the internal healing ability of the person that it impacts on their health and causes serious damage.
The coordinated team effort of patient, ETMS practitioner and oncologist is essential to ensure that the options, timing, and type of treatment are all taken into account at each stage to optimize outcomes.
Many people are worried about chemotherapy and herb interaction, believing the herbs will decrease the effectiveness of treatment when the truth of the matter is that the interaction is positive. The herbs not only protect healthy cells, and vital organs, and restore bone marrow health, but through a “multi-tasking” ability, the herbs potentiate and reduce drug resistance, as well as work alongside the cytotoxic drugs to target the multitude of abnormalities altered by cancer.
The four main objectives of chemotherapeutic drugs working synergistically with botanicals are as follows:
Rationale and Studies Supporting the Above Prostate Cancer Tests
Aromatase – an enzyme that catalyzes the conversion of androgens to estrogens.
The prostate expresses aromatase within the stroma of benign tissue, while in malignancy there is an induction of epithelial expression with altered promoter utilization. The presence of aromatase in the prostate and its aberrant expression in prostate cancer is significant and should be considered a target for prostate cancer treatment.
Bax – a protein that can promote apoptosis. Sulforaphane suppresses proliferation of prostate cancer cells by causing apoptosis via a complex signaling mechanism involving Bax activation, down regulation of IAP* family proteins and Apaf-1* induction. (Carcinogenesis. 2007)
*IAP (Inhibitor of Apoptosis Proteins) - Recent studies have documented the over-expression of anti apoptotic factors such as the inhibitors of apoptosis proteins (IAPs) in a variety of solid tumors and cancer cell lines. Eight human IAPs have been identified so far: NAIP (BIRC1), c-IAP1 (BIRC2), c-IAP2 (BIRC3), X-linked IAP (XIAP, BIRC4), Survivin (BIRC5), Apollon (BRUCE, BIRC6), Livin/ML-IAP (BIRC7) and IAP-like protein 2 (BIRC8). The members of IAP family, defined by the presence of a baculovirus IAP repeat (BIR) protein domain, are key regulators of apoptosis, cytokinesis and signal transduction. (Augello et al 2009)
*Apaf-1 (Apoptotic protease activating factor-1) is an essential factor in intrinsic mitochondrial pathway of apoptosis activation. Apaf-1 leads to the formation of apoptosome, which then proteolytically activates caspase-9. The activated caspase-9 opens the downstream signal of caspases to execute programmed cell death. Apaf-1 is important for tumor suppression and drug resistance because it plays a central role in DNA damage-induced apoptosis. Inactivation of the Apaf-1 gene is implicated in disease progression and chemoresistance of some malignancies. (He, Sun & Zhang 2009)
Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria which can prevent apoptosis by blocking cytochrome c release from mitochondria. Apoptotic cell death is triggered by down-regulation of Bcl-2 and cytochrome c release, and consequently the caspase cascade is activated to promote apoptosis. Licorice Glycyrrhiza glabra and its component licochalcone-A (LA) can induce autophagy in addition to apoptosis in human LNCaP prostate cancer cells. A novel polyphenolmolecule isolated from licorice root was also shown to induce Bcl-2 phosphorylation and apoptosis in prostate and breast cancer cells. Autophagy induction was accompanied by down-regulation of Bcl-2 and inhibition of the mammalian target of rapamycin (mTOR) pathway. (Yo et al 2009)
Bcl-2 is an NF-κB regulated gene that functions by blocking the apoptosis pathway, thus immortalizing cancer cells. It has been suggested that Bcl-2 over expression results in the up regulation of VEGF expression with increased neoangiogensis in human cancer xenografts.
Blood Chemistry Panel – standard blood test
Bone specific alkaline Phosphatase. Blood Test relating to cancer in the bone.
Bone specific alkaline phosphatase - Biochemical markers of bone resorption and bone formation are abnormally raised in the blood and urine of patients with metastatic bone disease. Markers of bone collagen breakdown, such as N-telopeptide, as well as markers of osteoblast function, such as bone specific alkaline phosphatase, appear to be of use in assessing and managing patients with malignancies that metastasize to bone. In this study, both N-terminal telopeptide (NTx) and bone-specific alkaline phosphatase (BAP) showed a significant correlation with both the presence of bone metastases and the extent of skeletal involvement. Biochemical markers of bone remodeling can also be used to guide decision making regarding the treatment of metastatic bone disease and to determine the effectiveness of therapy for patients with cancer to bone whose broad-based symptoms make it difficult to discern true response to therapy. (Demers et al, 2000)
BRCA-1 – This study gives evidence that BRCA1 differentially regulates IGF-IR expression in AR-positive and AR-negative prostate cancer cells. The mechanism of action of BRCA1 involves modulation of IGF-IR gene transcription. In addition, immunohistochemical data are consistent with a potential survival role of BRCA1 in prostate cancer. (Schayek H et al 2009)
BRCA1 and BRCA2 – are inherited breast cancer tumor suppressor genes that can be recognized on the human genome. BRCA1 and BRCA2 are found on chromosomes 17 and 13 respectively. Inherited mutations of these genes have been found to be associated with an increased risk of familial breast and ovarian cancer occurrences. Carriers of BRCA1 mutations have an increased risk of ovarian cancer (epithelial or transitional cell) and microglandular adenosis, and carriers of BRCA2 are at increased risk for Fanconi’s anemia, pancreatic cancer and prostate cancer. Persons with BRCA1 and BRCA2 mutations have an increased risk of breast cancer. Laboratory Tests and Diagnostic Procedures, p. 255 (2008)
Ceruloplasmin – Ceruloplasmin is sometimes a reflector of angiogenesis; and it is a good surrogate marker of body copper status. When it’s elevated it reflects that one of three growth factors are elevated – all of which are involved in prostate cancer – fibroblast growth factor (FGF), transforming growth factor beta, (TGF-β) and vascular endothelial growth factor (VEGF). Those three become dependent upon Ceruloplasmin. Donnie has never seen a case of cancer progressing with the Ceruloplasmin going down. So by lowering the estradiol and the Ceruloplasmin we’re diminishing the type of environment, the type of sequestering that goes on by the cancer to enable it to grow. Serum ceruloplasmin (Cp) increases in cancer patients; and may be a reliable marker for prostate cancer.
Ceruloplasmin - In all studied subjects with a prostate cancer, serum Ceruloplasmin (Cp) values were higher than age-matched healthy controls; they were also higher in cases with benign hyperplasia. There exists also a difference between benign hyperplasia cases and controls. It is suggested that serum Cp may complement the biochemical screening in prostate carcinoma, especially in cases where this cancer is not accompanied by elevation of serum PSA. However, it is not of help in differentiating prostate cancer from prostate benign hyperplasia. (Fotiou et al 2007)
Ceruloplasmin, zinc, copper and VEGF - By bringing zinc up it will bring Ceruloplasmin down. High Ceruloplasmin levels reflects high copper levels. High levels of ceruloplasmin also reflect upregulation of VEGF. (Donnie 8-7-09)
Ceruloplasmin is used to test for cancer (breast), cardiovascular disease, cirrhosis, diabetes mellitus, rheumatoid arthritis. Ceruloplasmin is an alpha2-globulin transport protein that transports copper and aids in mobilizing iron stores. It is an acute-phase reactant that becomes elevated during stress, pregnancy, and infection. ( Laboratory Tests and Diagnostic Procedures, p. 322 2008)
Both hypoxia and copper CuCl(2) increased ceruloplasmin (as well as vascular endothelial growth factor [VEGF] and glucose transporter 1 [Glut-1]) mRNA levels in hepatoma cells, which was due to transcriptional induction of the ceruloplasmin gene (CP) promoter. (Martin et al 2005)
Because the synthesis of ceruloplasmin is directly regulated by the bioavailability of copper to the liver, it is a good surrogate marker of body copper status. The copper in ceruloplasmin accounts for approximately 90% of the total plasma copper. (Goodman et al., 2004).
In general, copper is taken up into hepatocytes and incorporated into ceruloplasmin in the Golgi apparatus, and then it is secreted into the serum as holoceruloplasmin, a mature form of Ceruloplasmin. (Murata et al.,1995).
Chromogranin A – is an important blood marker to assess for prostate cancer. According to the Leibovitch study plasma chromogranin-A is a potential marker for diagnosis, monitoring and management of prostate cancer patients. (Leibovitch et al 2006)
Comprehensive Metabolic Panel – standard blood test
Copper – An excess of copper appears to be an essential co-factor for angiogenesis. Moreover, elevated levels of copper have been found in many types of human cancers, including prostate, breast, colon, lung, and brain. (Tisato et al 2009)
Many proangiogenic
cytokines, such as vascular endothelial growth factor (VEGF),
fibroblast growth factor, IL-6, and IL-8, are copper-dependent.
One mechanism of suppression of cytokine signaling is through
inhibition of nuclear factor-B (NF-κB). (Pan et al.,
2002)
COX-2 – There is no argument that COX-2, LOX(especially 5-LOX) and PPARγ are involved in the initiation and promotion of prostate cancer tissues. The administration of COX-2 and 5-LOX inhibitor, and PPAR-γ ligand are useful along with conventional treatment of human prostate cancer. The combination therapy of COX-2 and 5-LOX inhibitor, and PPAR-γ ligand may be a benefical new treatment of human prostate cancer. (Matsuyama and Yoshimura 2008)
COX-2 - Most common cancers with altered (amplified) COX-2 expression include: prostate, colon, breast, cervical brain, gastric, pancreatic, lung, head and neck, kidney and bladder.
C-peptide –High C-peptide and the response of the insulin is not only problematic to cardiovascular health but very problematic in cancer, being that two of the promotional effectors of prostate cancer are insulin and insulin growth factors, namely IGF-1 and IGF-2, which both relate to insulin. They both increase proliferation and inhibit apoptosis. They both allow angiogenesis to a degree.
C-peptide - Men with C-peptide concentrations in the highest quartile (high) versus the lowest quartile (low) had a higher risk of prostate cancer mortality. Excess bodyweight and a high plasma concentration of C-peptide both predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of this disease. (Ma et al, 2008)
C-Reactive Protein - C-reactive protein is associated with high PSA as a marker of metastatic prostate cancer but not with overall cancer risk. (Eklund et al, 2009) Inflammation plays a major role in driving prostate cancer progression and in its resistance to therapy. (Stark 2006) The level should be <.8.
CTCs - Circulating tumor cells (CTC) have been recently accepted by the Food and Drug Administration of the United States as a prognostic tool in advanced prostate cancer. Herein the authors describe their experience with the CellSearch method of CTC enumeration. The authors conclude that baseline CTC values provide important prognostic information and specific prediction of metastatic disease. Their presence correlates with classic biomarkers. (Goodman et al 2009)
CTCs - Circulating tumor cells predict survival benefit from treatment in Metastatic Castration- Resistant Prostate Cancer (de Bono et al 2008)
D-Dimer test – will tell you if you might have a clot somewhere in your body, or risk forming a clot. 0-1 is good and indicates no clot indicated. The higher above the 1 you get, the more the likelihood of a clot. The range Donnie likes to see is below 0.40. Plasma D-dimer levels have been shown to be increased in patients with various solid tumors including lung, prostate, cervical, ovarian, breast and colon cancer.
D-Dimer - Compared to healthy male controls, patients with prostate cancer had significantly increased levels of both D-dimer and tissue factor (TF)-specific PCA of plasma microparticles(MPs). Collectively, our findings suggest that TF-specific procoagulant activity of plasma MPs contributes to intravascular coagulation activation in patients with early-stage prostate cancer and may represent a potential link between hypercoagulability, inflammation, and disease progression. (Haubold et al 2009)
DHT (dihydrotestosterone) - Dihydrotestosterone, a product converted from testosterone by 5alpha-reductases, plays an important role in normal prostate growth and in the development of prostate cancer (PCa). The 5alpha-reductase levels, particularly type 1, appear to increase during the disease course of prostatic intraepithelial neoplasia and PCa, with greater expression occurring as the disease progresses. Therefore, the inhibition of 5alpha-reductase could potentially reduce the risk of PCa development, slow or prevent disease progression, and/or treat existing disease. (Crawford 2009)
Donnie likes to see the DHT levels under 30.
EGFR (Epidermal Growth Factor Receptor) – In prostate cancer, inhibition of EGFR signaling can result in a significant growth reduction and in increased apoptosis in EGFR-expression PCa cells with different modalities which are regulated by PTEN status and this may have relevance in the clinical setting of PC. (Festuccia et al 2005)
Estradiol – is proliferative to prostate cancer as well as problematic for men generally. It doesn’t do anything positive for a man to have higher estradiol levels. It has nothing but negative ramifications. But typically, when insulin is high and C-peptide is high the production of aromatase – an enzyme which goes along with that whole kind of scenario – starts making high amounts of estrogen as well. So then you have both high insulin levels and high estrogen levels creating this whole environment that is much more conducive to the growth of cancer.
Estradiol – Evidence suggests that 17beta-estradiol (E2) contributes to the risk of prostate cancer. (Smith et al 2008) In high-grade prostatic intraepithelial neoplasia the estrogen receptor alpha is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. (Bonkhoff and Berges 2008)
Fibrinogen – Donnie likes it under 350. When the plasminogen activator inhibitor (PAI) is upregulated then I know it’s a pathway relating to the cancer. But what I have found is that when people have the C-peptide high and the insulin high and when I bring those down the fibrinogen also comes down.
Fibroblast growth factor (FGF)-2 is a critical growth factor in normal and malignant cell proliferation and tumor-associated angiogenesis. Fibrinogen and fibrin bind to FGF-2 and modulate FGF-2 functions. These data indicate that endogenously synthesized fibrinogen promotes the growth of lung and prostate cancer cells through interaction with FGF-2. (Sahni et al 2008)
Free/total PSA – standard prostate test
PSA velocity - PSA velocity refers to the serial evaluation of serum PSA concentration over time. This PSAV cutoff was mainly useful in patients with a PSA level between 4 and 10 ng ml-1, yielding specificity greater than 90%. Infection and chronic inflammation can also be confounding factors as they can cause significant increases in PSA. It is therefore recommended that a minimum of three consecutive PSA measurements should be made over a 2-year period. More recent studies evaluated the PSA velocity prior to PCa treatment to predict tumor stage, grade and time to
recurrence after radical prostatectomy. D'Amico and associates reported significantly shorter time to PSA relapse and death from PCa in patients with a pretreatment annual PSA velocity of more than 2.0 ng ml-1 among 1054 patients who underwent radical prostatectomy for localized PCa. Other studies confirmed that annual PSA velocity prior to diagnosis is a promising approach to identify candidates who may not benefit from local therapy.
Gleason score - The Gleason grading system, based on prospective study of more than 4000 patients between 1960 and 1975, is the standard method of grading prostate cancer throughout the world. The Gleason grading system is based on the degree of architectural differentiation. A primary pattern is assigned for the dominant grade and a secondary pattern for the nondominant grade; the Gleason score is obtained by adding these two values. The value of histological grading of prostate cancer after radiation therapy or hormonal therapy is controversial. A trend toward higher Gleason score after radiation therapy has been observed. A number of hypothesis have been suggested to account for this finding, including (1) cancer progression and tumor dedifferentiation following radiation therapy and (2) sampling variation in pre-irradiation biopsies and preferential progression of high-grade cancer. fig 26 The most important feature to be evaluated in post-radiation prostate biopsies is the extent of treatment effect. The Gleason grading system was originally based upon the architectural pattern of untreated cancer and is not applicable to histological changes resulting from treatment. Application of the Gleason grade to radiation treated prostates can only create confusion and must be avoided as has been recently recommended by the College of American Pathologists.
HbA1c- this tells us if the sugar is damaging the body.
HbA1c is a reflection of how well blood glucose levels have been controlled for up to the previous 4 months. (Laboratory Tests and Diagnostic Procedures 2008, p. 594)
IGF-1 – Recent evidence suggests that androgens, leptin, IL-6, VEGF, insulin and IGF-1 may play a role in prostate cancer progression, while adiponectin and IGFBP-3 may act as "anti-prostatic cancer" adipokines. (Lopez et al 2009)
Circulating levels of intact IGFBP3 measured after diagnosis is associated with increased risk of prostate cancer-specific death. (Johanssen et al 2009)
Insulin-like growth factor binding protein-3 (IGFBP-3), a major IGF-binding protein in human serum, regulates the growth of several cancers, including prostate, through IGF-dependent and IGF-independent mechanisms. IGFPB-3 effectively blocks uPA- and matrix metalloproteinase-2-stimulated invasion pathways, ultimately reducing cancer cell metastasis. IGFBP-3 may be a key pathway as an anti-invasive and antimetastatic therapeutic agent for cancer. (Oh et al 2006)
IL-6 - Higher Gleason score correlated with high levels of conditioned medium derived interleukin-6. Moreover, cell signaling analysis of periprostatic adipose tissue identified activated signaling molecules, including STAT3, that correlated with Gleason score. Since STAT3 is interleukin-6 regulated, these findings suggest that periprostatic adipose tissue may have a role in modulating prostate cancer aggressiveness by serving as a source of interleukin-6. Also, we found low numbers of inflammatory cells in the fat, suggesting that adipocytes are the major secretors. (Finley et al 2009)
IL-6 - High circulating levels of leptin, interleukin 6, and VEGF are associated with increased prostate cancer risk and increased aggressiveness. (Mistry et al 2007)
Recent evidence suggests that androgens, leptin, IL-6, VEGF, insulin and IGF-1 may play a role in prostate cancer progression, while adiponectin and IGFBP-3 may act as "anti-prostatic cancer" adipokines. (Lopez et al 2009)
IL-6 & IL-8 - In both in vivo and in vitro experimental studies on prostate bone tumors it was found that increases in secretion of pro-inflammatory cytokines (ie, interleukin-6, -8) coincident with overexpression of cathepsin K suggest possible mechanisms by which this enzyme contributes to tumor progression in the bone. (Podgorski et al 2009)
Many proangiogenic
cytokines, such as vascular endothelial growth factor (VEGF),
fibroblast growth factor, IL-6, and IL-8, are copper-dependent.
One mechanism of suppression of cytokine signaling is through
inhibition of nuclear factor-B (NF-κB). (Pan et al.,
2002)
Insulin (fasting) – Recent evidence suggests that androgens, leptin, IL-6, VEGF, insulin and IGF-1 may play a role in prostate cancer progression, while adiponectin and IGFBP-3 may act as "anti-prostatic cancer" adipokines. (Lopez et al 2009)
In Donnie’s experience it should always be under 10. Insulin levels reflect the C-peptide levels. So if the insulin is high then the C-peptide is high. That means that things like the PPARγ in particular are not working well.
Insulin resistance has a role in metabolic syndrome physiopathology. Our study suggests that metabolic syndrome may exert an influence on the development of prostate cancer. (de Santana et al 2008)
High levels of glucose can elevate blood insulin levels, causing IGF to increase, which leads to oxidative stress and activates NF-κB, causing inflammation.
Ki-67 - When a tumor cell tests positive for Ki-67, the tumor is actively growing. Most prostate cancers typically have very low percentages of growing cells and they grow slowly. The greater the proportion of prostate tumor cells with Ki-67, the more aggressive the cancer. Their study conclusively shows that Ki-67 was the most significant determinant of distant metastasis and death in prostate cancer patients. In addition, Ki-67, along with PSA, Gleason score and stage, appears to be valuable in determining whether high-risk patients may be spared long-term androgen deprivation. (Pollack et al 2003)
Leptin - High circulating levels of leptin, interleukin 6, and VEGF are associated with increased prostate cancer risk and increased aggressiveness. (Mistry et al 2007)
Recent evidence suggests that androgens, leptin, IL-6, VEGF, insulin and IGF-1 may play a role in prostate cancer progression, while adiponectin and IGFBP-3 may act as "anti-prostatic cancer" adipokines. (Lopez et al 2009)
Leptin -- is a cellular signaling compound involved with weight gain. It is designed to replenish the body’s store of fat after a period of deprivation. Malfunctioning leptin causes major health problems. These include insulin resistance, high blood pressure, high cholesterol, diabetes, heart disease, increased risk for several forms of cancer, etc.
Lipid profile – If the triglycerides are 130 this is the highest Donnie allows them to be. He likes them to be under 140, but he’d like them even lower. So at 130 that also reflects the insulin and C-peptide.
LOX (lipoxygenase) - While 5- and 12-LOX expressions were slightly detected in benign prostatic hyperplasia and normal prostate tissues, marked expressions of 5- and 12-lipoxygenase were detected in prostatic intraepithelial neoplasia and prostate cancer tissues. The LOX inhibitors caused marked reduction of prostate cancer cells in a concentration- and time-dependent manner. The LOX inhibitors caused marked inhibition of PC cells through apoptosis. LOX is induced in prostate cancer, and our results suggest that LOX inhibitors may mediate potent antiproliferative effects against prostate cancer cells. Thus, LOX may become a new target in treatment of prostate cancer. ( Matsuyama et al 2004)
LOX –Several LOX pathways are up-regulated in practically all cancers. Currently there are no drugs which block LOX-5 pathways
NF-κB - (Nuclear Factor-kappaB) - The detection of NF-kappaB-mediated TGF-beta-induced epithelial-mesenchymal transition (EMT) in primary tumors predicts disease recurrence in prostate cancer patients following radical prostatectomy. The changes in TGF-beta signaling and EMT-related factors provide novel molecular markers that may predict prostate cancer outcomes following treatment. (Zhang et al 2009)
NF-κB1 - NF-kappaB activation plays a critical role in prostate cancer by NF-kappaB inhibitor kinase beta pathway-mediated inflammatory-induced tumorigenesis. Prostate cancer patients with a history of prostatitis have a 2.275 times higher risk for prostate cancer, compared to the control group. The functional NFκB1 promoter polymorphism is associated with increased risk of prostate cancer. (Zhang et al 2009)
Many proangiogenic
cytokines, such as vascular endothelial growth factor (VEGF),
fibroblast growth factor, IL-6, and IL-8, are copper-dependent.
One mechanism of suppression of cytokine signaling is through
inhibition of nuclear factor-B (NF-κB). (Pan et al.,
2002)
Osteocalcin - expression is restricted to osteoblasts and serum osteocalcin level is elevated in metastatic bone tumors including prostate tumors, which predominantly metastasizes to the bone and causes typical osteoblastic lesions. This study explains why serum osteocalcin level is increased in patients with bone-metastasized prostate cancers. Yet, it remains to be clarified what regulates bone-specific osteocalcin RNA splicing in prostate tumors. (Gardner et al 2009)
Osteocalcin – is a gamma-carboxylated protein of bone matrix that is used as a serum marker of bone turnover because it is specifically produced by the osetoblast. Osteocalcin is an integral part of the bone formation process; however, a small amount of osteocalcin does enter the circulation. The circulating levels of osteocalcin are a specific indicator of recent bone turnover. (Laboratory Tests and Diagnostic Procedures,2008, pages 830-831)
p21 - The data in this study suggest that increased p21(WAF1/CIP1) production directly suppresses proliferation of prostate cancer cells regardless of androgen sensitivity. (Sugibayashi et al 2002)
p27- Thrombin stimulates tumor cell growth in LNCaP prostate cancer cells in vivo by down-regulation of p27(Kip1). (Hu et al 2009)
p27 - Homeodomain transcription factor Nkx3.1 is a putative prostate tumor suppressor that is expressed exclusively in the prostate under the regulation of androgen, and p27(KIP1) functions as a cell proliferation inhibitor and apoptosis trigger by disrupting the cyclin-dependent kinase (CDK)-cyclin complex. p27(KIP1) overexpression in PC3 results in increased cell population ceased at the G0/G1 phase, and this cell-cycle-arresting effect is significantly enhanced by the coexpression of Nkx3.1. Flow cytometry further revealed that Nkx3.1 and p27(KIP1) also cooperatively render more PC3 cells undergoing apoptosis. Consistently, the coexpression of Nkx3.1 and p27(KIP1) leads to the decreased expression of Bcl-2 oncogene and a concomitantly upregulated Bax expression. It also activates caspase 3 and leads to increased cleavage of PARP. Our findings thus reveal the crucial relevance of the combined antiproliferative and proapoptotic activities of Nkx3.1 and p27(KIP1) in androgen-independent PC cells, and further suggest that a combined, rather than single gene manipulation may be of clinical value for hormone-refractory PC. (Wang et al 2009)
p53 – The highest frequency of p53 mutations reported in human cancers are lung, 56%; colon, 50%; esophagus,45%; ovary, pancreas and skin, 44%; stomach, 41%; head and neck, 37%; bladder, 34%; prostate, 30% and breast, endometrium and mesothelioma, 22%.
p-Akt - The phosphorylated Akt (p-Akt), a phosphoinositide-3-OH-kinase (PI3K) activated protein kinase, is highly expressed in prostate tumors. P-Akt can indirectly hinder p53-dependent growth suppression and apoptosis by phosphorylating Mdm2*. (Han, Schoene & Lei 2009)
*Mdm family proteins are crucial regulators of the oncosuppressor p53. Alterations of their gene status, mainly amplification events, have been frequently observed in human tumors. (Mancini, Conza & Moretti 2009)
PAP - Prostatic Acid Phosphatase –Serum activity of PAP is greatly increased in metastatic cancer of the prostate in which the tumor has extended beyond the capsule surrounding the prostate gland. Therefore this test is used as both a marker for and a monitor of the disease course.(Laboratory Tests and Diagnostic Procedures 2008, p.913) PAP is an important blood tumor marker to assess prostate cancer.
PCA3 molecular urine test - The prostate cancer 3 (PCA3) gene was discovered in 1999, on the basis of differential expression between cancer and noncancerous prostate tissue. Including the first study published in 2003, 11 clinical studies have evaluated its utility for the diagnosis of prostate cancer by measuring the number of PCA3 RNA copies in urine enriched with prostate cells. Although the sensitivity of the PCA3 test was less than that of serum prostate-specific antigen (PSA), its specificity appeared to be much better, particularly in patients with a previous negative biopsy. Recent studies also have suggested that this test could be used to predict cancer prognosis. (Vlaeminck-Guillem et al 2009)
PPARγ - Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear hormone receptor superfamily of transcription factors. Peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in the regulation of lipid homeostasis, adipogenesis, insulin resistance, and development of various organs. Agonists of PPARγ have been also reported to inhibit proliferation of prostate carcinoma cells as in other human malignancies. PPARγ immunoreactivity is considered to be a new clinicopathological parameter of human prostate cancer. (Nakamura et al 2009)
PTEN - Conditional deletion of PTEN* in the mouse prostate causes deregulated induction of survivin before full-blown transformation in vivo, whereas expression of survivin and PTEN is inversely correlated in cancer patients. Therefore, silencing the survivin gene is an essential requirement of endogenous PTEN tumor suppression. (Guha et al 2009)
* PTEN – Phosphatase and tensin homologue – is a tumor suppressing gene.
o When it mutates it is the likely driver that activates NF-κB.
o PTEN mutations, or lost expression of, relates to: The activation of NF-κB, COX-2 and EGFR. It relates to poor prognosis and resistance to chemotherapy, hormone therapy and herceptin therapy.
SEPP (Selenoprotein P) - Selenium (Se) is essentially needed for the biosynthesis of selenoproteins. Low Se intake causes reduced selenoprotein biosynthesis and constitutes a risk factor for tumorigenesis. Accordingly, some Selenium supplementation trials have proven effective to reduce prostate cancer risk, especially in poorly supplied individuals. Because Se metabolism is controlled by selenoprotein P (SEPP), we have tested whether circulating SEPP concentrations correlate to prostate cancer stage and grade. We conclude that decreased SEPP concentration in serum might represent an additional valuable marker for prostate cancer diagnostics. (Cancer Epidemiol Biomarkers Prev 2009;18(9):OF1-5) (For complete abstract see Appendix.)
Survivin is an NF-kB regulated gene that functions by blocking the apoptosis pathway, thus immortalizing cancer cells.
Survivin - The expression of survivin, a member of the inhibitor-of-apoptosis (IAP) family (see p. 3 for definition of IAP), is elevated in various human cancers originating in the breast, lung, prostate, colon, pancreas and stomach and is the result of p53 mutation.
Testosterone, Total; Testosterone, Free and Total -
TGFβ (Transforming Growth Factor-beta) - The detection of NF-kappaB-mediated TGF-beta-induced epithelial-mesenchymal transition (EMT) in primary tumors predicts disease recurrence in prostate cancer patients following radical prostatectomy. The changes in TGF-beta signaling and EMT-related factors provide novel molecular markers that may predict prostate cancer outcomes following treatment. (Zhang et al 2009)
Transforming Growth Factor Beta -1 (TGFβ-1) is a major marker to test in prostate cancer. It strongly corresponds to survival in prostate cancer.
uPA - urokinase-type plasminogen activator system in prostate cancer. Expression levels of uPA and uPAR were significantly associated with major prognostic indicators, including pathological stage, Gleason score, lymphatic invasion, surgical margin status and lymph node metastasis. However, PAI-1* expression was related to only pathological stage and surgical margin status, and there was no significant association between the expression level of PAI-2 and several parameters examined. Therefore the authors conclude that the uPA system may be involved in the progression of prostate cancer, and that the expression level of uPA in prostate cancer tissue could be used as a useful predictor of biochemical recurrence in patients undergoing radical prostatectomy RP. (Kumano et al 2009)
* PAI-1 – Plasminogen activator inhibitor-1 is the major inhibitor of fibrinolysis. When PAI-1 is high, fibrinolytic activity is depressed, and there is increased risk for arterial and venous thrombosis. PAI-1 may serve to protect cancer tissue against the proteolytic degradation triggered by the tumor on surrounding normal tissue. Furthermore, the inhibitor has a role in angiogenesis, which has an important part to play in tumor spread.
VEGF - High circulating levels of leptin, interleukin 6, and VEGF are associated with increased prostate cancer risk and increased aggressiveness. (Mistry et al 2007)
Recent evidence suggests that androgens, leptin, IL-6, VEGF, insulin and IGF-1 may play a role in prostate cancer progression, while adiponectin and IGFBP-3 may act as "anti-prostatic cancer" adipokines. (Lopez et al 2009)
VEGF - Both hypoxia and copper CuCl(2) increased ceruloplasmin (as well as vascular endothelial growth factor [VEGF] and glucose transporter 1 [Glut-1]) mRNA levels in hepatoma cells, which was due to transcriptional induction of the ceruloplasmin gene (CP) promoter. (Martin et al 2005)
VEGF - Platelets involved in tumour angiogenesis are capable of releasing vascular endothelial growth factor (VEGF). (Gil-Bazo et al 2005)
Many proangiogenic
cytokines, such as vascular endothelial growth factor (VEGF),
fibroblast growth factor, IL-6, and IL-8, are copper-dependent.
One mechanism of suppression of cytokine signaling is through
inhibition of nuclear factor-B (NF-κB). (Pan et al.,
2002)
Vitamin D - The autocrine synthesis of 1alpha,25(OH)2D3 from vitamin D3 suggests that maintaining adequate levels of serum vitamin D could be a safe and effective chemo-preventive measure to decrease the risk of prostate cancer. (Flanagan et al 2006) Vitamin D deficiency increases risk of prostate cancer. According to our recent results, the key Vitamin D hormone involved in the regulation of cell proliferation in prostate is 25(OH) Vitamin D3. (Lou et al 2004)
Zinc - The prostate contains the highest concentration of zinc of all the soft tissues, but concentrations decrease significantly during prostate cancer. A growing body of experimental evidence supports the notion that high zinc levels are essential for prostate health and may limit prostate cancer development. The possible mechanisms include the effects of zinc on the inhibition of terminal oxidation, induction of mitochondrial apoptogenesis and suppression of NF-κB activity. Zinc may also play an important role in the maintenance of DNA integrity in normal prostate epithelial cells by modulating DNA repair and damage response proteins, especially p53. In addition, recent findings support the role of zinc transporters as tumor suppressors in the prostate. Although epidemiological studies have shown mixed results, the experimental data strongly suggest a protective role of zinc in the prostate. (Ho and Song 2009)
Zinc – This study found that zinc treatments haled the growth of the prostate cancer tumors and substantially extended the survival of the animals, whilst causing no detect able cytotoxicity to other tissues. This study concludes that it forms a sold proof-of-concept that direct intra-tumoral injection of zinc acetate could be a safe and effective treatment strategy for prostate cancer. (Shah MR et al 2009)
Actions of Cancer Preventive Botanicals & Nutrients on Selected Cancer Targets
Bcl-2
Licorice Glycyrrhiza glabra and its component licochalcone-A (LA) can induce autophagy in addition to apoptosis in human LNCaP prostate cancer cells. A novel polyphenolmolecule isolated from licorice root was also shown to induce Bcl-2 phosphorylation and apoptosis in prostate and breast cancer cells. Autophagy induction was accompanied by down-regulation of Bcl-2 and inhibition of the mammalian target of rapamycin (mTOR) pathway. (Yo et al 2009)
· Natural Compounds that Down-Regulate Bcl-2
COX-2
There is no argument that COX-2, LOX(especially 5-LOX) and PPARγ are involved in the initiation and promotion of prostate cancer tissues. The administration of COX-2 and 5-LOX inhibitor, and PPAR-γ ligand are useful along with conventional treatment of human prostate cancer. The combination therapy of COX-2 and 5-LOX inhibitor, and PPAR-γ ligand may be a benefical new treatment of human prostate cancer. (Matsuyama and Yoshimura 2008)
Most common cancers with altered (amplified) COX-2 expression include: prostate, colon, breast, cervical brain, gastric, pancreatic, lung, head and neck, kidney and bladder.
Natural Compounds that Down-Regulate COX-2
· Several foods and common culinary herbs contain particular compounds that reduce inflammation, in part, by acting as COX-2 inhibitors. These include grapes (leaf and skin), curcumin longo (turmeric), Ocimun sanctum (basil), fish, flax, oregano, rosmarinus (rosemary) and licorice root (glycyrrhizin glabra).
EGFR (Epidermal Growth Factor Receptor)
In prostate cancer, inhibition of EGFR signaling can result in a significant growth reduction and in increased apoptosis in EGFR-expression PCa cells with different modalities which are regulated by PTEN status and this may have relevance in the clinical setting of PC. (Festuccia et al 2005)
Natural compounds shown to block EGF receptor activation and its downstream effectors include:
NFκB ( Nuclear Factor Kappa B)
The detection of NF-kappaB-mediated TGF-beta-induced epithelial-mesenchymal transition EMT in primary tumors predicts disease recurrence in prostate cancer patients following radical prostatectomy. The changes in TGF-beta signaling and EMT-related factors provide novel molecular markers that may predict prostate cancer outcomes following treatment. (Zhang et al 2009)
Natural Compounds that Down-Regulate or Inhibit NFκB
P53 Mutation
The highest frequency of p53 mutations reported in human cancers are lung, 56%; colon, 50%; esophagus,45%; ovary, pancreas and skin, 44%; stomach, 41%; head and neck, 37%; bladder, 34%; prostate, 30% and breast, endometrium and mesothelioma, 22%. (Greenblat et al 1994)
Natural compounds that normalize p53
PDGF Mutation
PDGF (platelet-derived growth factor) signaling plays a crucial role for cell growth, tumorigenesis, and cell differentiation. Expression of PDGF, and activation (by autophosphorylation) of its receptor (PDGFR), a tyrosine kinase, is associated with the growth of metastasis in several forms of cancer including kidney, breast, prostate, sarcomas, cervical and in head and neck cancer.
Natural compounds that suppress PDGF
PTEN
Conditional deletion of PTEN in the mouse prostate causes deregulated induction of survivin before full-blown transformation in vivo, whereas expression of survivin and PTEN is inversely correlated in cancer patients. Therefore, silencing the survivin gene is an essential requirement of endogenous PTEN tumor suppression. (Guha et al 2009)
Known activators of PTEN and/or inhibitors of PTEN mutation include:
Survivin
DIM- Inactivation of survivin by Diindylmethane (DIM) enhanced the therapeutic efficacy of Taxotere in prostate cancer in general, which could be useful for the treatment of hormone-refractory prostate cancer and metastatic prostate cancer. (Rahman et al 2009)
uPA (Urokinase Plasminogen Activator)
Nutraceutical compounds that inhibit uPA
Several potential uPA inhibitors have been identified such as antipain, leupeptin, folic acid, rosmarinic acid (from rosemary), lavendustin A, fisetin, myricetin, and tolfenamic acid. Both a proper diet rich in uPA-inhibiting nutraceuticals and plant-based concentrated supplements can become a supportive tool in prostate cancer treatment.74 Part of the antitumor and antiangiogenic mechanisims of soy isoflavones involves an ability to down-regulate uPA.75 Genistein has also demonstrated effective reductions in uPA expression.76
VEGF
High circulating levels of leptin, interleukin 6, and VEGF are associated with increased prostate cancer risk and increased aggressiveness. (Mistry et al 2007)
Herbs and Compounds that Inhibit VEGF
Research on the Actions of Specific Herbs on Prostate Cancer
Saw Palmetto
1. Saw palmetto berry extract inhibits cell growth and COX-2 expression in prostatic cancer cells. (Goldmann et al 2001)
2. Saw Palmetto is an effective dual inhibitor of 5alpha-reductase isoenzyme activity in the prostate. Unlike other 5alpha-reductase inhibitors, saw palmetto induces its effects without interfering with the cellular capacity to secrete PSA. (Habib et al 2005)
3. Saw Palmetto extract treatment may relieve symptoms of BPH, in part, by inhibiting specific components of the IGF-1 signaling pathway and inducing JNK activation, thus mediating anti-proliferative and pro-apoptotic effects on prostate epithelia. (Wadsworth et al 2004)
4. Human PC3 and LNCaP prostate cancer cells and MCF7 breast cancer cells treated with saw palmetto extract underwent selective apoptosis, whereby cell death only occurred in the prostate cancer cells. Within minutes saw palmetto extract caused opening of the permeability transition pore (PTP), selectively inducing apoptotic cell death of prostate cancer cells. (Baron et al 2006)
5. In androgen-independent PC3 prostate cancer cells, saw palmetto, lipido-sterolic extract administration exerted a biphasic action by both inhibiting proliferation and stimulating apoptosis. (Petrangeli et al 2009)
6. Saw palmetto, lycopene and selenium all inhibit prostate cancer though a dual activity, inhibition of proliferation as well as on inflammation within the prostate gland. (Magri et al 2008)
7. Saw palmetto berry extract, and its sterol components, beta-sitosterol and stigmasterol, inhibit prostate cancer growth and are potential anti-tumor agents. (Scholtysek et al 2009)
8. Treatment with saw palmetto in vitro resulted in a 33% decrease of PC-3 cell proliferation at 72 hours and a 23% reduction of DU-145 cell proliferation at 24 hours. This study clearly demonstrates a biologic response to saw palmetto treatment as manifested by cell proliferation and tumor growth. (MacLaughlin et al 2006)
Milk Thistle (Silibinin/Silymarin)
1. The underlying mechanisms of silibinin/silymarin efficacy against prostate cancer involve alteration in cell cycle progression, and inhibition of mitogenic and cell survival signaling, such as epidermal growth factor receptor, insulin-like growth factor receptor type I and nuclear factor kappa B signaling. Silibinin also synergizes the therapeutic effects of doxorubicin in prostate cancer cells, making it a strong candidate for combination chemotherapy. (Singh & Agarwal 2004)
2. Silibinin possess anticancer activity against both hormone-dependent and -independent prostate cancer. Studies aiming at testing in vivo efficacy of silymarin/ silibinin conducted revealed that dietary feeding of silibinin to animals bearing prostate cancer significantly inhibits tumor growth and increases secreted levels of insulin-like growth factor binding protein 3 (IGFBP-3) in plasma without any toxicity symptoms in the animals fed with silibinin. (Singh et al 2002) Other in vitro studies confirms that silibinin upregulates the expression of IGFBP-3, and thus causes increase secreted IGFBP-3 in conditioned medium. (Zi et al 2000) Cell survival signaling and proliferation is partially mediated by IGFBP-insulin like growth factor-1 factor-1 (IGF-1)/IGF-1R (insulin like growth factor-1 receptor) is often constitutively upregulated in human prostate carcinoma cell lines and is often implicated in advanced and androgen independent stage of prostate cancer. (Johansson et al 2007)
3. Silymarin and silibinin (50-100 microg/ml) inhibited cell proliferation, induced cell death, and caused G1 and G2-M cell cycle arrest in a dose/time-dependent manner in prostate cancer cells. Also noted was a decrease in cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase (CDK)4, CDK6 and CDK2 protein levels, and CDK2 and CDK4 kinase activity, together with an increase in CDK inhibitors (CDKIs) Kip1/p27 and Cip1/p21. Further, both agents caused cytoplasmic sequestration of cyclin D1 and CDK2, contributing to G1 arrest. (Deep et al 2006)
4. The antiangiogenic effects of silymarin were also exemplified in a study whereby exposure of DU145 prostate, as well as MCF-7 and MDA-MB-468 breast cancer cells to silymarin resulted in a dose-dependent decrease in the secreted vascular endothelial growth factor (VEGF). (Jiang, Agarwal & Lu 2000)
5. The androgen sensitive prostate cancer cell line LNCaP is strongly positive for dihydrotestosterone (DHT) dependent telomerase activity, which is an important factor in cellular immortality and carcinogenesis. In a recent study the potential of silibinin as an anticancer agent was examined and demonstrated an ability to down-regulate telomerase activity and PSA levels. The down-regulation of PSA by silibinin and its counteraction on DHT effects indicate that this compound can interact with the expression of genes that are regulated through the androgen receptor. (Kohno et al 2005)
6. Silibinin strongly synergized the growth-inhibitory effect of doxorubicin in prostate carcinoma DU145 cells, which was associated with a strong G(2)-M arrest in cell cycle progression, showing 88% cells in G2-M phase by this combination compared with 19 and 41% of cells in silibinin and doxorubicin treatment alone, respectively. Silibinin and doxorubicin alone as well as in combination were also effective in inhibiting the growth of androgen-dependent prostate carcinoma LNCaP cells. Positive outcomes might be relevant for a clinical application in prostate cancer patients. (Tyagi, Singh & Agarwal 2002)
Crataeva Nurvala (Crateva)
1. Lupeol: Active compound in Crateva - Collectively, these data suggest the multitarget efficacy of Lupeol on beta-catenin-signaling network thus resulting in the inhibition prostate cancer cell proliferation. We suggest that Lupeol could be developed as an agent for chemoprevention as well as chemotherapy of human prostate cancer. (Saleem et al 2009) Crateva extract should contain a mininium of 1.5% lupeol, 25% saponins, and 2% tannins.
2. Lupeol - is a triterpene, found in fruits and vegetables which was shown to inhibit the growth of tumors originated from human androgen-sensitive prostate cancer cells and to decrease the serum-PSA levels in a mouse model. This study concluded that the Lupeol-induced growth inhibition of prostate cancer cells is a net outcome of simultaneous effects on stathmin, cFLIP, and survivin which results in the disruption of microtubule assembly. We suggest that Lupeol alone or as an adjuvant to other microtubule agents could be developed as a potential agent for the treatment of human prostate cancer. (Saleem et al 2009)
Lycopene
1. Lycopene likely prevents prostate cancer development by acting as a redox coupling agent, regulating IGF signaling, and Intercellular Gap Communication. As part of a recent clinical trial, men were provided tomato sauce-based pasta dishes for 3 weeks before radical prostatectomy for prostate cancer. (Gann et al 1999) For these men, tomato consumption was associated with increased lycopene levels in the blood and in the prostate, with decreased oxidative genome damage in leukocytes and in prostate cells, and with a reduction in serum PSA. (Chen et al 2001)
2. Lycopene, sulforaphane, and diindole methane (DIM) - High intake of tomatoes, (Kaia et al 2004) which contain lycopene, and of cruciferous vegetables, (Verhoven et al 1996) which contain sulforaphane, and diindole methane (DIM) are protective against prostate cancer development. (Hadley et al 2002)
3. Lycopene and Green Tea - This study suggests that habitual drinking of green tea and intakes of vegetables and fruits rich in lycopene could lead to a reduced risk of prostate cancer. (Jian, Lee & Binns 2007)
4. Silymarin, soy isoflavones concentrate, and lycopene - In a human study involving men with prostate cancer taking a supplement that included Silymarin, soy isoflavones concentrate, and lycopene a 2.6 fold increase in the PSA doubling time from 445 to 1150 days for the supplement and placebo periods was found. (Schroder et al 2005)
Pygeum africanum
1. This study provides a molecular insight for atraric acid (AA) isolated from bark material of Pygeum africanum as a natural anti-androgenic compound and may serve as a basis for AA derivatives as a new chemical lead structure for novel therapeutic compounds as androgen receptor (AR) antagonists, that can be used for prophylaxis or treatment of prostatic diseases. (Papaioannou M, et al 2008)
2. Pygeum africanum, which is widely used in Europe and USA for treatment of BPH, has a significant role in regulation of prostate cancer both in vitro and in vivo and therefore may be a useful supplement for people at high risk for developing prostate cancer. (Shenouda NS, et al 2007)
Pumpkin Seed Oil
Pumpkin seed oil can inhibit testosterone-induced hyperplasia of the prostate in rats and therefore may be beneficial in the management of benign prostatic hyperplasia. (Gossel-Williams et al 2006)
Selenium
1. Selenium - This study showed that there was a significant inverse association between selenium levels and overall prostate cancer risk. However, on further analysis, only the association with advanced cancer, not localized disease, was significant. (Redman et al 1997)
2. Selenium and genistein - This study demonstrates that selenium and genistein act via different molecular mechanisms and exhibit enhanced anticancer effects, suggesting that a combination of selenium and genistein may offer better efficacy and reduction of toxicity in prostate cancer prevention. (Zhao et al 2009)
Urtica dioica (Nettles)
1. Adenosine deaminase (ADA) inhibition by Urtica dioica extract might be one of the mechanisms in the observed beneficial effect of Urtica dioica in prostate cancer. (Durak et al 2004)
2. In the present study, Urtica dioica has beneficial effects in the treatment of symptomatic benign prostatic hypertrophy. (Safarinejad MR 2005)
Zinc
1. Zinc – This study found that zinc treatments haled the growth of the prostate cancer tumors and substantially extended the survival of the animals, whilst causing no detect able cytotoxicity to other tissues. This study concludes that it forms a sold proof-of-concept that direct intra-tumoral injection of zinc acetate could be a safe and effective treatment strategy for prostate cancer. (Shah MR et al 2009)
2. Zinc - The prostate contains the highest concentration of zinc of all the soft tissues, but concentrations decrease significantly during prostate cancer. A growing body of experimental evidence supports the notion that high zinc levels are essential for prostate health and may limit prostate cancer development. The possible mechanisms include the effects of zinc on the inhibition of terminal oxidation, induction of mitochondrial apoptogenesis and suppression of NF-κB activity. Zinc may also play an important role in the maintenance of DNA integrity in normal prostate epithelial cells by modulating DNA repair and damage response proteins, especially p53. In addition, recent findings support the role of zinc transporters as tumor suppressors in the prostate. Although epidemiological studies have shown mixed results, the experimental data strongly suggest a protective role of zinc in the prostate. (Ho and Song 2009)
Other Prostate Cancer Preventive Botanicals
Andrographolide - Andrographolide, a diterpenoid lactone isolated from a traditional herb (Andrographis paniculata), is known to possess potent anti-inflammatory activity. This study showed that it induced apoptosis of prostate cancer via the activation of caspase 3, up-regulation of bax, and down-regulation of bcl-2. Furthermore, its inhibitory activity on the level of vascular endothelial growth factor (VEGF) was also verified by ELISA. (Zhao et al 2008) Andrographolide is in Inflamaway.
Artemisinin - a naturally occurring component of Artemisia annua, or sweet wormwood, is a potent anti-malaria compound that has recently been shown to have anti-proliferative effects on a number of human cancer cell types, although little is know about the molecular mechanisms of this response. Our results demonstrate that a key event in the artemisinin anti-proliferative effects in prostate cancer cells is the transcriptional down-regulation of CDK4 expression by disruption of Sp1 interactions with the CDK4 promoter. (Willoughby et al 2009)
Artemisinin - This study demonstrated that artemisinin-tagged transferrins (ART-Tf) conjugate kills the prostate carcinoma cell line DU 145 by the mitochondrial pathway of apoptosis. (Nakase et al 2009)
DIM (3,3'-diindolylmethane) - The p75(NTR) functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. We identify DIM as an indole capable of inducing p75(NTR)-dependent apoptosis via the p38 MAPK pathway in prostate cancer cells. (Khwaja et al 2009)
Honokiol - – Exposure of human prostate cancer cells (PC-3, LNCaP, and C4-2) resulted in apoptosis, irrespective of their androgen responsiveness or p53 status. (Hahm et al 2008) Honokiol is in Inflamaway.
Honokiol - Here we show that Honokiol, a natural dietary product isolated from an extract of seed cones from Magnolia grandiflora, can decrease PI3K/mTOR pathway-mediated immunoresistance of glioma, breast and prostate cancer cell lines, without affecting critical proinflammatory T cell functions. (Crane et al 2009)
Phenethyl isothiocyanate (PEITC) and its effects on IL-6-induced STAT3 activity:
This study was undertaken to investigate the mechanism by which phenethyl isothiocyanate (PEITC), a natural compound from cruciferous vegetables, exhibits antitumor effect on prostate cancer cells. Our data demonstrated that PEITC can inhibit the activation of the JAK-STAT3 signal-cascade in prostate cancer cells and the underlying mechanism may be partially involved with blocking cellular ROS production during the early stage of the signaling activation by IL-6. (Gong et al 2009)
Pomegranate – The following is from a Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer: Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. The authors sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy. They report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study. (Pantuck et al 2006)
Quercetin - Our results demonstrate that quercetin down-regulates the expression of Hsp90 which, in turn, induces inhibition of growth and cell death in prostate cancer cells while exerting no quantifiable effect on normal prostate epithelial cells. (Aalinkeel et al 2008)
Resveratrol - Our laboratory and others have demonstrated the antiprostate cancer (anti-CaP) activity of resveratrol, as evident in its suppression of cell proliferation, arrest of cell cycle progression, and induction of apoptosis in androgen-responsive LNCaP and androgen-non-responsive DU145 and PC-3 CaP cells. To our knowledge, this study is the first to reveal that resveratrol targeting protein NQO2 plays a mediating role in resveratrol-induced changes of NF-kappaB p65, which may contribute to the anti-CaP activities elicited by resveratrol. (Hsieh 2009)
Low-/nonfat milk - A study published in the American Journal of Epidemiology found no association between the intakes of calcium and Vitamin D and prostate cancer risk, but low-/nonfat milk consumption was moderately associated with higher risk and whole milk consumption was associated with slightly decreased risk of prostate cancer. (Park et al 2007)
Prostate Tumor Hypoxia May Confer Resistance to Radiotherapy
Hypoxia in prostate tumors significantly predicts a poor long-term biochemical outcome, independent of other factors such as tumor stage or Gleason score, according to results of a study presented by Dr. Benjamin Movsas at the American Society of Clinical Oncology's annual meeting in Orlando, Fl. May 29, 2009.
A recent meta-analysis showed that neither neoadjuvant nor adjuvant androgen deprivation combined with prostatectomy improves biochemical control, or disease-free and overall survival. (Jereczek-Fossa BA, Curigliano G, Orecchia R. 2009)
Melatonin has been shown to have potent anti-proliferative effects in various cancer cells such as breast and prostate cancer cells. Melatonin exerts the inhibitory effect of the proliferation of RA-FLSs (rheumatoid arthritis fibroblast-like synoviocytes) through the activation of P21 and P27 mediated by ERK (extracellular signal-regulated protein kinase). (Nah et al 2009)
Reduced Serum Selenoprotein P Concentrations in German Prostate Cancer Patients
Selenoprotein P (SEPP) - Selenium (Se) is essentially needed for the biosynthesis of selenoproteins. Low Se intake causes reduced selenoprotein biosynthesis and constitutes a risk factor for tumorigenesis. Accordingly, some Se supplementation trials have proven effective to reduce prostate cancer risk, especially in poorly supplied individuals. Because Se metabolism is controlled by selenoprotein P (SEPP), we have tested whether circulating SEPP concentrations correlate to prostate cancer stage and grade. A total of 190 men with prostate cancer (n = 90) and "no evidence of malignancy" (NEM; n = 100) histologically confirmed by prostate biopsy were retrospectively analyzed for established tumor markers and for their Se and SEPP status. Prostate specific antigen (PSA), free PSA, total Se, and SEPP concentrations were determined from serum samples and compared with clinicopathologic parameters. The diagnostic performance was analyzed with receiver operating characteristic curves. Median Se and SEPP concentrations differed significantly (P < 0.001) between the groups. Median serum Se concentrations in the 25th to 75th percentile were 95.9 mug/L (82-117.9) in NEM patients and 81.4 mug/L (67.9-98.4) in prostate cancer patients. Corresponding serum SEPP concentrations were 3.4 mg/L (1.9-5.6) in NEM and 2.9 mg/L (1.1-5.5) in prostate cancer patients. The area under the curve (AUC) of a marker combination with age, PSA, and percent free PSA (%fPSA) in combination with the SEPP concentration, yielded the highest diagnostic value (AUC 0.80) compared with the marker combination without SEPP (AUC 0.77) or %fPSA (AUC 0.76). We conclude that decreased SEPP concentration in serum might represent an additional valuable marker for prostate cancer diagnostics.(Cancer Epidemiol Biomarkers Prev 2009;18(9):OF1-5). (Meyer et al 2009)
Tomato products and soy protein - A study was completed to determine if men with active prostate cancer will adhere to a dietary intervention rich in tomato products and a soy protein supplement men (n = 41) with recurrent, asymptomatic prostate cancer were randomized among 2 groups: Group A (n = 20) consumed tomato products (no soy) for Weeks 0 through 4, targeting a minimum of 25 mg of lycopene/day. Group B (n = 21) consumed soy (no tomatoes) for Weeks 0 through 4, providing 40 g of soy protein/day. For Weeks 4 through 8, all men consumed a combined tomato-rich diet and soy supplements. No grade II through IV toxicities were observed. During Weeks 0 through 4, mean daily lycopene intake for Group A was 43 mg (+/- 15 mg) and mean soy intake for Group B was 39 g (+/- 1 g), remaining similar during Weeks 4 through 8. Serum lycopene increased from 0.72 +/- 0.09 micromol/l to 1.21 +/- 0.10 micromol/l (P < 0.0001) and urinary isoflavone excretion increased from not detectable to 54.1 +/- 5.7 micromol/l (P < 0.05) with 8 wk of diet intervention. Serum prostate-specific antigen decreased between Weeks 0 and 8 for 14 / 41 men (34%). Mean serum vascular endothelial growth factor for the entire group was reduced from 87 to 51 ng/ml (P < 0.05) over 8 wk. (Grainger et al 2008)
Lupeol inhibits prostate cancer in vivo and decreases serum PSA: Inhibits ERBB2 (Her II neu), MMP-2 and 3, and beta-catenin
Lupeol inhibits the proliferative potential of prostate cancer (CaP) cells and delineated its mechanism of action. Employing a focused microarray of human CaP-associated genes, we found that Lupeol significantly modulates the expression level of genes such as ERBB2, tissue inhibitor of metalloproteinases-3, cyclin D1 and matrix metalloproteinase (MMP)-2 that are known to be associated with proliferation and survival. A common feature of these genes is that all of them are known to either regulate or act as downstream target of beta-catenin signaling that is highly aberrant in CaP patients. Lupeol treatment significantly (1) reduced levels of beta-catenin in the cytoplasmic and nuclear fractions, (2) modulated expression levels of glycogen synthase kinase 3 beta (GSK3beta)-axin complex (regulator of beta-catenin stability), (3) decreased the expression level and enzymatic activity of MMP-2 (downstream target of beta-catenin), (4) reduced the transcriptional activation of T Cell Factor (TCF) responsive element (marker for beta-catenin signaling) in pTK-TCF-Luc-transfected cells and (5) decreased the transcriptional activation of MMP-2 gene in pGL2-MMP-2-Luc-transfected cells. Effects of Lupeol treatment on beta-catenin degradation were significantly reduced in CaP cells where axin is knocked down through small interfering RNA transfection and GSK3beta activity is blocked. Collectively, these data suggest the multitarget efficacy of Lupeol on beta-catenin-signaling network thus resulting in the inhibition prostate cancer cell proliferation. We suggest that Lupeol could be developed as an agent for chemoprevention as well as chemotherapy of human prostate cancer. (Saleem et al 2009)
Lupeol in Crateva Suppresses Prostate cancer
A study was conducted that investigated the growth-inhibitory effect and associated mechanisms of Lupeol, in androgen-sensitive human prostate cancer cells. Lupeol treatment resulted in significant inhibition of cell viability in a dose-dependent manner and caused apoptotic death of prostate cancer cells. Lupeol was found to induce the cleavage of poly(ADP-ribose) polymerase protein and degradation of acinus protein with a significant increase in the expression of FADD protein. Among all death receptor targets examined, Lupeol specifically caused a significant increase in the expression of Fas receptor. The small interfering RNA-mediated silencing of the Fas gene and inhibition of caspase-6, caspase-8, and caspase-9 by their specific inhibitors confirmed that Lupeol specifically activates the Fas receptor-mediated apoptotic pathway in androgen-sensitive prostate cancer cells. The treatment of cells with a combination of anti-Fas monoclonal antibody and Lupeol resulted in higher cell death compared with the additive effect of the two compounds alone, suggesting a synergistic effect. Lupeol treatment resulted in a significant inhibition in growth of tumors with concomitant reduction in prostate-specific antigen secretion in athymic nude mice implanted with CWR22Rnu1 cells. Lupeol appears to have potential against prostate cancer. (Saleem et al 2005)
Inhibition of prostate cancer: Lupeol with mango pulp extract
A study was conducted that investigated the apoptogenic activity in mouse prostate by lupeol and mango pulp extract (MPE). Testosterone was injected subcutaneously (5 mg/kg body weight) for 14 consecutive days to male Swiss albino mice. Lupeol/MPE supplementation resulted in arrest of prostate enlargement in testosterone-treated animals. In mouse prostate tissue, lupeol and MPE supplementation resulted in a significantly high percentage of apoptotic cells in the hypodiploid region. The induction of apoptosis in mouse prostate cells was preceded by the loss of mitochondrial transmembrane potential and DNA laddering. In testosterone-induced mouse prostate, upregulation of antiapoptotic B-cell non-Hodgkin lymphoma-2 and downregulation of proapoptotic Bcl-2-associated X protein and caspase-3 were also recorded. We further observed apoptogenic activities of lupeol in an in vitro model using human prostate cancer cells [lymph node carcinoma of the prostate (LNCaP)]. The apoptogenic response of lupeol-induced changes in LNCaP cells can be summarized as early increase of reactive oxygen species followed by induction of mitochondrial pathway leading to cell death. Lupeol/MPE is effective in combating testosterone-induced changes in mouse prostate as well as causing apoptosis by modulating cell-growth regulators. (Prasad, Kalra & Shukla 2008)
Lupol: Active compound in Crateva
Lupeol, a pentacyclic triterpene isolated from the root bark of crateva, has been shown to significantly minimize the deposition of stone-forming constituents in kidneys. Investigations have also indicated the plant has anti-arthritic, hepatoprotective, and cardio-protective actions. (Bopana & Saxena 2008)
d-Limonene - Background: Clinical trials have shown that docetaxel combined with other novel agents can improve the survival of androgen-independent prostate cancer patients. d -Limonene, a non-nutrient dietary component, has been found to inhibit various cancer cell growths without toxicity. We sought to characterize whether a non-toxic dose of d -limonene may enhance tumor response to docetaxel in an in vitro model of metastatic prostate cancer. Materials and Methods: Human prostate carcinoma DU-145 and normal prostate epithelial PZ-HPV-7 cells were treated with various concentrations of d -limonene, docetaxel or a combination of both, and cell viability was determined by MTT assay. Intracellular reactive oxygen species (ROS), reduced glutathione (GSH) and caspase activity were measured. Apoptosis and apoptosis-related proteins were studied by enzyme-linked immunosorbent assay and Western blotting, respectively. Results: d -Limonene and docetaxel in combination significantly enhanced the cytotoxicity to DU-145 cells than PZ-HPV-7 cells. Exposure of DU-145 cells to a combined d -limonene and docetaxel resulted in higher ROS generation, depletion of GSH, accompanied by increased caspase activity than docetaxel alone. It also triggered a series of effects involving cytochrome c, cleavages of caspase-9, 3 and poly (ADP-ribose) polymerase, and a shift in Bad:Bcl-xL ratio in favor of apoptosis. Apoptotic effect was significantly blocked on pretreatment with N -acetylcystein, indicating that antitumor effect is initiated by ROS generation, and caspase cascades contribute to the cell death. Conclusion: Our results show, for the first time, that d -limonene enhanced the antitumor effect of docetaxel against prostate cancer cells without being toxic to normal prostate epithelial cells. The combined beneficial effect could be through the modulation of proteins involved in mitochondrial pathway of apoptosis. d -Limonene could be used as a potent non-toxic agent to improve the treatment outcome of hormone-refractory prostate cancer with docetaxel. (Rabi & Bishayee 2009)
D-limonene is one of the most common terpenes in nature. It is a major constituent in several citrus oils (orange, lemon, mandarin, lime, and grapefruit). D-limonene is listed in the Code of Federal Regulations as generally recognized as safe (GRAS) for a flavoring agent and can be found in common food items such as fruit juices, soft drinks, baked goods, ice cream, and pudding. D-limonene is considered to have fairly low toxicity. It has been tested for carcinogenicity in mice and rats. Although initial results showed d-limonene increased the incidence of renal tubular tumors in male rats, female rats and mice in both genders showed no evidence of any tumor. Subsequent studies have determined how these tumors occur and established that d-limonene does not pose a mutagenic, carcinogenic, or nephrotoxic risk to humans. In humans, d-limonene has demonstrated low toxicity after single and repeated dosing for up to one year. Being a solvent of cholesterol, d-limonene has been used clinically to dissolve cholesterol-containing gallstones. Because of its gastric acid neutralizing effect and its support of normal peristalsis, it has also been used for relief of heartburn and gastroesophageal reflux (GERD). D-limonene has well-established chemopreventive activity against many types of cancer. Evidence from a phase I clinical trial demonstrated a partial response in a patient with breast cancer and stable disease for more than six months in three patients with colorectal cancer. (Sun J 2007)
Books
Monographs
Online
Home ׀ Health News ׀ Treatments ׀ Articles ׀ Links ׀ Disclaimer ׀ Forms/Directions
Compassionate Acupuncture & Healing Arts, 4501 Valley Forge Rd., Durham, NC 27705 Tel. 919-309-7753 Email: compassionateacu@mindspring.com
Copyright © 2009 John G. Connor