Understanding Prostate Cancer

Natural Strategies in Collaborative Cancer Care

by John G.Connor, M.Ac., L.Ac.

edited by Barbara Connor, M.Ac., L.Ac.

April 6, 2011

 Table of Contents

• Introduction
• Natural Strategies in Collaborative Cancer Care
• Examples of Natural Compounds that Inhibit Prostate Cancer
• Dietary Considerations in Prostate Cancer
• Understanding Androgen Deprivation Therapy
• Examples of Natural Compounds that Target Growth Factors & Genes Involved in Prostate Cancer
• Comprehensive Cancer Care Consultations
• References

Introduction

 

Despite advances in screening and local therapy, prostate cancer remains the second most common cause of cancer related death among American men, with those having high grade disease being at highest risk for prostate cancer mortality. (Ross et al 2011)

 

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)

 

Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

 

Barbara and I feel that the emerging concept and practice of targeted therapies which have a high specificity toward tumor cells provides a broader therapeutic window with less toxicity than the current chemotherapeutic agents. 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. 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, receptor tyrosine kinase inhibitors, and growth factor receptor inhibitors.

 

The wonderful thing about botanicals and nutritives is that they target many of the same growth factors, receptors and pathways as conventional drugs and chemos but in a gentler and less toxic way thereby allowing for decreased dosages in the more toxic chemos and drugs. One of the characteristics of plants is that they are pleiotrophic, i.e., they exert multiple effects. Therefore botanicals and herbs by their very nature not only enhance the effectiveness of chemos and drugs but they can reduce or eliminate many of their unwanted side effects.

 

In a recent study functional themes associated with Gleason grade include developmental processes, signal transduction, chemokine and embryonic stem cell pathways with specific enrichment of the androgen receptor, EGFR, TNF-alpha, and Notch signaling cascades. (Ross et al 2011)

 

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

 

Natural Strategies in Collaborative Cancer Care

 

The following is a list of natural strategies we employ and the issues we address in our approach to integrative cancer care:

 

·         Alkalinity and Acidosis in Cancer

·         Angiogenesis Blood Markers

·         Appendix of Cancer Pathways

·         Blood Tests for Cancer-Related Cachexia

·         Blood Tests that Detect Various Polymorphisms that Relate to the Metabolism or Detoxification of Chemotherapy

·         Blood Tests to Assess Hypercoagulation

·         Bone Building Protocol for Bone Related Cancer

·         Cancer and Sugar

·         Chemotherapy and Predictive Bio-markers

·         Copper Reduction Protocol

·         Counteracting Cancer Related Cachexia with Natural Compounds

·         Cytotoxic Herbs & Their Functions

·         Factors that Increase the Risk of Blood Clots and Thrombosis.

·         Glossary of Chemotherapeutic Drugs

·         Growth Factors and Genes Involved in Cancer

·         How Elevated Glucose and Insulin Promote Cancer

·         Immunotherapy - Activating the Immune System with Natural Compounds

·         Inflammatory Blood Markers

·         Inhibiting Angiogenesis with Natural Compounds

·         Managing the Side Effects of Chemotherapy with Natural Compounds

·         Markers for Assessing Bone Health

·         Natural Aromatase Inhibitors

·         Natural Compounds that Act as Biological Response Modifiers

·         Natural Compounds That Alleviate the Side Effects of Chemobrain

·         Natural Compounds that are Radiation Protective or Synergistic with Radiation Therapy

·         Natural Compounds that Downregulate HPV

·         Natural Compounds that Downregulate IGF and are Insulinotrophic, and Anti-cancer.

·         Natural Compounds that Enhance the Effectiveness of Paclitaxel

·         Natural Compounds that Enhance the Effectiveness of Platinums

·         Natural Compounds that Inhibit Multi Drug Resistance

·         Natural Compounds that Lower Homocysteine

·         Natural Compounds that Protect against Bone Cancer

·         Natural Compounds that Protect against the Side Effects of Doxorubicin

·         Natural Compounds that Reduce the Side Effects of Carboplatin

·         Natural Compounds that Reduce the Side Effects of Paclitaxel

·         Natural Compounds that Reduce the Side Effects of Platinol (Cisplatin)

·         Natural Compounds that Reduce the Side Effects of Platinum Drugs

·         Natural Compounds that Synergize with Doxorubicin (Anthracyclines)

·         Natural Compounds that Target Growth Factors and Genes Involved in Cancer

·         Natural Compounds which Hasten Recovery from Surgery

·         Neuropathy and Cancer Pain Management

·         Nutritional Support for Glutathione and Optimal Liver Detoxification

·         Radiation and Cancer

·         Reducing Inflammation with Natural Compounds

·         Suppressing Hypercoagulation with Natural Compounds

·         Surgery and Cancer

·         Teas and Soups which Alleviate the Side Effects of Chemo and What to Eat During Chemo

·         Tissue Pathology Reports

·         Understanding the Mechanism behind Bone Metastasis

 

Examples of Natural Compounds that Inhibit Prostate Cancer

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) 

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)

Boron - In the last few years boron (B) compounds became increasingly frequent in the chemotherapy of some forms of cancer with high malignancy and of inoperable cancers. Types of cancers most frequently impacted by B-containing compounds include prostate, breast, cervical and lung cancer. Boron-enriched diets resulted in significant decrease in the risk for prostate and cervical cancer, and decrease in lung cancer in smoking women. (Scorei & Popa 2010)

Broccoli - Consuming broccoli interacts with GSTM1 (glutathione S-transferase mu 1) genotype to result in complex changes to signalling pathways associated with inflammation and carcinogenesis in the prostate. We propose that these changes may be mediated through the chemical interaction of isothiocyanates with signalling peptides in the plasma. This study provides, for the first time, experimental evidence obtained in humans to support observational studies that diets rich in cruciferous vegetables may reduce the risk of prostate cancer and other chronic disease (Traka et al 2008)

Crataeva Nurvala  - (Lupeol is the 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)

 

Curcumin - Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Our results suggest that curcumin is an interesting chemopreventive agent for early stage prostate cancer. (Teitan et al 2011)

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)

DIM induces apoptosis in prostate cancer cells via the mitochondria- and death receptor-mediated pathways. (Cho et al 2011)

 

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)

 

IP6 (inositol hexaphosphate) – causes G(1) arrest and increases cyclin-dependent kinase inhibitors p21/Cip1 and p27/Kip1 protein levels in human prostate cancer (PCa) DU145 cells lacking functional p53. (Roy et al 2009)

 

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) In Serenoa Supreme

 

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)

 

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)

 

Omega-3 Fatty Acids - Dietary intake of fish and omega-3 polyunsaturated fatty acids (omega-3 PUFAs) may decrease the risk of prostate cancer development and progression to advanced stage disease. The literature suggests that fish, and particularly long-chain omega-3 PUFAs, may have a more pronounced protective effect on biologically aggressive tumors or on their progression, and less on early steps of carcinogenesis. Overall, results to date support the hypothesis that long-chain omega-3 PUFAs may impact prostate inflammation and carcinogenesis via the COX-2 enzymatic pathway. (Reese 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)

 

Pygeum africanum - 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)

 

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)

 

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)

 

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)

 

Vitamin E and Selenium - VES, i.e., vitamin E (+-alpha-tocopheryl succinate, or MSA, i.e., selenium (methylselenic acid) alone led to a modest inhibition in the viability and growth of PCa cells. However, a combination of these two agents resulted in a dramatic increase in growth inhibition of PCa cells. Interestingly, VES and/or MSA were not found to have any effect on the growth or viability of normal PrEC cells. VES and MSA treatment to human PCa cells resulted in (i) induction of apoptosis, (ii) increase in Bax, Bak, and Bid proteins, and (iii) decrease in Bcl-2 protein. (Reagan-Shaw et al 2008)

 

Vitamin K(2) (menaquinone) - Cancer risk reduction with increasing intake of menaquinonses was more pronounced in men than in women, mainly driven by significant inverse associations with prostate and lung cancer in the EPIC-Heidelberg (European Prospective Investigation into Cancer and Nutrition-Heidelberg) cohort study, which included 24,340 participants. These findings suggest that dietary intake of menaquinones, which is highly determined by the consumption of cheese, is associated with a reduced risk of incident and fatal cancer. (Nimptsch et al 2010)

Zinc – This study found that zinc treatments halted the growth of the prostate cancer tumors and substantially extended the survival of the animals, whilst causing no detectable 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

 

Dietary Considerations in Prostate Cancer

 

Examples of Recommended Foods in Prostate Cancer:

1. Ground flaxseeds – inhibit VEGF (a procancerous growth factor). They also lower cholesterol and triglycerides as well as prevent ER+ breast cancer.
2. Broccoli sprouts - eat 1-2 handfuls in salad 2-3x a week.  Broccoli is rich in sulforaphane which prevents prostate cancer. (Choi et al 2007)
3. Cooked tomato products (organic) 3x per week.  They contain lycopene which prevents prostate cancer by regulating IGF signaling. (Gann et al 1999)
4. Avocado – 3-4x a week – suppresses prostate cancer. (Lu et al 2005)

 

Understanding Androgen Deprivation Therapy

 

Androgen Deprivation Therapy (ADT) - Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. For late stage disseminated disease however, current therapies are merely palliative and no curative treatment exists. Since the growth of prostate tumors is originally androgen-dependent, metastatic cancers are generally treated with androgen ablation therapy, with or without antiandrogen supplementation. The vast majority of these patients show a significant clinical regression, but the cancer eventually recurs within 12–18 months. These recurrent tumors have escaped androgen suppression and become resistant to hormonal therapy, referred to as hormone-refractory or castration-resistant Prostate Cancer (PCa). (Marques et al 2010)

 

Long term androgen deprivation therapy for prostate cancer is associated with a 30-40% increased risk of colorectal cancer. (Gillessen et al 2010)

 

Low Testosterone - Among men who have coronary heart disease, mortality was doubled in those with low testosterone levels compared with those who had normal levels, a new observational study has shown. (Malkin et al 2010 )

 

Low Testosterone - Importantly, some longitudinal epidemiological studies reported that men with low testosterone have reduced survival, with an increase in all-cause, cardiovascular, cancer and respiratory mortality, compared to men with higher or normal testosterone levels. (Jones 2010)

 

A review of major adverse effects of androgen-deprivation therapy in men with prostate cancer found significant elevations in the risk of diabetes. The review also found that men who underwent ADT for prostate cancer had a significantly increased risk of overall fracture of 23% compared with men who had prostate cancer but who did not undergo ADT. Furthermore, men who underwent ADT had a 17% increase in cardiovascular-related mortality compared with men who did not undergo with ADT.  Preventive measures against these adverse effects and careful assessment of patient's baseline health status should be considered. (Taylor et al 2009)

 

Androgen Deprivation Therapy - Men with prostate cancer can be at increased risk for CAD (cardiovascular disease) due to long-term androgen deprivation therapy (ADT) administered as treatment for prostate cancer. Commercially available LHRH agonists are goserelin, (Zoladex), histrelin, leuprolide, and triptorelin. We found that the increased risk for serious cardiovascular disease becomes evident within months of beginning ADT. Pharmacists should provide counseling to these patients on primary disease prevention. Men receiving ADT should be monitored routinely for signs and symptoms of metabolic syndrome, diabetes, and CAD. Healthy lifestyle practices should be encouraged, and physical therapy should be considered for these patients. (Kintzel et al 2008)

 

Low Testosterone - Testosterone insufficiency in older men who were followed for 20 years is associated with increased risk of death, independent of multiple risk factors and several preexisting health conditions. (Laughlin et al 2008)

 

Androgen Deprivation Therapy - is associated with significantly increased cardiovascular morbidity in men with prostate cancer and may lower overall survival in men with low-risk disease. These data have particular relevance to decisions regarding the use of ADT in men with prostate cancer in settings in which the benefit has not been clearly established. For men with metastatic disease, focused efforts to reduce cardiac risk factors through diet, exercise, or the use of lipid-lowering agents may mitigate some of the risks of ADT. (Saigal et al 2007)

 

The dual 5-α reductase enzyme inhibitor dutasteride (Avodart) - In the present pilot study, treatment with dutasteride resulted in a significant decrease in serum PSA in men with serologic relapse following radical treatment for adenocarcinoma of the prostate. These data appear to suggest that dutasteride may delay or prevent progression of prostate cancer in some men with biochemical relapse after radical therapy. (Perrotti et al 2010)

d-Limonene - 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. 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. 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)

Thymoquinone – a component of Nigella sativa or black cumin - is a naturally occurring herbal product.  It may prove to be effective in treating hormone-sensitive as well as hormone-refractory prostate cancer. Furthermore, because of its selective effect on cancer cells, we believe that thymoquinone can also be used safely to help prevent the development of prostate cancer. (Kaseb et al 2007)

 

Examples of Natural Compounds that Target Growth Factors and Genes Involved in Prostate Cancer

 

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)

 

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)

 

Examples of Natural compounds shown to block EGF receptor activation and its downstream effectors include:

1.       Curcumin – Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Our results suggest that curcumin is an interesting chemopreventive agent for early stage prostate cancer. (Teitan et al 2011)

2.      Vitamin D-3 – in colon cancer. (Tong et al 1999) and in some breast cancer cells (McGaffin et al 2004)

 

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 Inhibit or Down-Regulate NF-kappaB:

1. Alpha lipoic acid inhibits NF-κB activation.
2. DIM - significantly inhibited Akt activation, NF-kappaB DNA binding activity and PSA targeting multiple pathways involved in prostate cancer. (Bhuiyan et al 2006) (Banerjee et al 2009)– In Cell Guardian
3. N-acetyl cysteine (NAC) (Sailai et al 2010) NAC enhanced hypoxia-induced caspase-3 activation and apoptosis in part by way of inhibition of hypoxia-induced NF-kappaB. (Qanungo et al 2004)
4. Panax ginseng (Jou et al 2009) and panax notoginseng (Son et al 2009)
5. Parthenolide (Feverfew) (Nehra et al 2010) (Riggins et al 2005)
6. Vitamin D3 – reduced NF-kappaB in prostate cancer cells. (Bao et al 2006)

 

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)

 

In prostate cancer, there appears to be a strong dependence on PI3K signaling for survival, as these cells tend to acquire mutations in PTEN, a negative regulator of PI3K signaling (Bertram et al., 2006; Edick et al., 2007; Lin et al., 1999b; Wen et al., 2000). This suggests that prostate cancer might arise from a more differentiated cell that has already acquired dependence on PI3K for its survival. (Lamb et al 2010)

 

Natural Compounds which Activate PTEN and/or Inhibit PTEN Mutation

1. Genistein - When MCF-7 cells were stimulated with resveratrol, quercetin or genistein, there was an increase in PTEN protein levels. (Waite et al 2005)
2. Quercetin – When MCF-7 cells were stimulated with resveratrol, quercetin or genistein, there was an increase in PTEN protein levels. (Waite et al 2005)
3. Resveratrol – Increases PTEN (Waite et al 2005) (Hum Mol Genet. 2005 June & Int J Cancer 2009 Jul)