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Understanding Colon Cancer

Compiled by John Connor, L.Ac. from articles & lectures by Donald Yance and other selected sources – Nov. 18, 2009

 

Table of Contents

 

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.

 

Background to Colon Cancer

·        Colon cancer is one of the most common inherited cancer syndromes known. Among the genes found to be involved in colorectal cancer are: MSH2 and MSH6 both on chromosome 2 and MLH1, on chromosome 3. Normally, the protein products of these genes help to repair mistakes made in DNA replication. If the MSH2, MSH6, and MLH1 proteins are mutated and therefore don't work properly, the replication mistakes are not repaired, leading to damaged DNA and, in this case, colon cancer.

 

·        Recent animal studies have suggested that colorectal tumors expressing a Ras mutation produce significant amounts of COX-2.  This is of note since Ras mutations are involved in the production of late stage adenomas and eventual loss of chromosome 18.

 

·        HER-2 protein is over expressed in 11% of colorectal cancer patients.  The gene encoding HER-2 is amplified in 3% of cases.  Over expression of HER-2 is not a predictor of outcome.  However, patients who over express HER-2 may respond to Herceptin therapy. (Kavanagh et al 2009)

 

·        MTHFR C677T genotype – (MTHFR - methylene tetrahydrofolate reductase).  The MTHFR C7677T mutation appears to interact with folate in determining cancer risk, and there may be further interaction with riboflavin status.  The effect of this mutation on cancer risk may be site specific in that individuals carrying the TT variant appear to be protected against colorectal cancer.

o       Genetic variation in MTHFR but not TYMS may be useful for predicting toxicity from capecitabine in patients with advanced colorectal cancer.

 

Tissue Pathology and Blood Tests to Perform on Colon Cancer Cells

·        Pathology Tests

o       EGFR – (epidermal growth factor receptor)

o       ERCC1 – (excision repair cross-complementing factor 1)

o       KI-67

o       KRAS – (K-ras gene)

o       p53 –

o       TS -  (thymidylate synthetase)

 

·        Blood Tests

o       CA-19-9

o       CEA

o       Ceruloplasmin

o       Copper

o       C-reactive protein

o        CTCs - circulating tumor cells

o       D-Dimer

o       ESR (erythrocyte sedimentation rate)

o       Fibrinogen

o        HGB A1C - (Hemoglobin A1-C)

o       Homocysteine 

o       LDH (lactate dehydrogenase)

o       PAI-1 - Plasminogen activator inhibitor- 1

o       Serum insulin (fasting) & IGF-1

o       VEGF - vascular endothelial growth factor

o       Vitamin D (25 OH)

o       Zinc

 

Rationale and Studies Supporting the Use of the Above Markers

·        CA 19-9 – This test is used to monitor gastrointestinal, pancreatic and colorectal malignancies. Normal levels are <37 AU/mL.  Metastasis levels are >1000 AU/mL. Laboratory Tests and Diagnostic Procedures, p. 270 (2008)

 

·        CA-19-9 – an  important blood tumor marker to assess colon and pancreatic cancers

 

·        Carcinoembryonic Antigen (CEA) – is a helpful marker in establishing prognosis, determining effectiveness of therapy and recognizing recurrent disease in patients with adenocarcinoma, especially those arising in the colon or stomach (elevated in 25% of cases).  CEA is the marker of choice for monitoring colorectal carcinoma, and levels above15 ng/ml indicate high-risk patients and the need for adjuvant or neoadjuvant chemotherapy.  It is likely that CEA facilitates metastasis of colorectal carcinoma cells to the liver and lung. High preoperative levels are associated with metastatic disease and poorer prognosis. Laboratory Tests and Diagnostic Procedures, p. 293 (2008)

 

·        CEA – carcinoembryonic antigen.  CEA tests are used to help predict overall survival in cancer. In a study involving resection of colorectal liver metastases, the authors found that the change in CEA level 6 weeks after resectional surgery, was a strong predictor of 5-year survival.  This information could prove useful in selecting patients for the use or non-use of adjuvant chemotherapy. (Oussoultzoglou 2008)

 

·        CD-34 – a pathology protein expression. High levels predict lower chances of survival in colorectal cancer.

 

·        Ceruloplasmin – Ceruloplasmin is sometimes a reflector of angiogenesis; and it relates to copper often too.  But 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, 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.

 

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)

 

By bringing zinc up it will bring Ceruloplasmin down.  It reflects high copper.  It also reflects upregulation of VEGF-- one of the primary growth factors in colon cancer. (Donnie 8-7-09)

 

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).

 

·        Copper – High serum levels of copper correlate with certain cancers and high copper appears to play a role in cancer promotion. The angiogenic activity of bFGF (basic fibroblast growth factor), VEGF, TNF-α (Tumor necrosis factor alpha) and IL-1 (Interleukin-1) were found to be copper dependent. 

 

 

·        Copper (serum) and ceruloplasmin levels were estimated in 20 patients each of prostate and colon cancer. Although copper to ceruloplasmin ratio was not significantly altered, copper and ceruloplasmin levels were increased significantly in the cancer patients as compared to controls. Trace elements and free radicals have been implicated in the etiology of cancer. Hence determination of specific antioxidants (like ceruloplasmin) and trace elements (like copper) may be of value in the early diagnosis of prostate and colon cancer. (Navak et al 2003)

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-{kappa}B (NF;κB).  (Pan et al., 2002)

 

 

·        CRP - High levels of C-reactive protein (CRP) were found associated with poor prognosis and low levels with good prognosis in patients with colorectal cancer. CRP -- is part of the inflammatory process and reflects the level of inflammatory activity.  It is associated with inflammation related to insulin resistance.  Levels should be below 0.8.

 

·        CTCs (circulating tumor cell) – The number of CTCs before and during treatment is an independent predictor of progression-free survival and overall survival in patients with metastataic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies.  (Cohen 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.

 

·        D-dimer levels (plasma) have been shown to be increased in patients with various solid tumors including lung, prostate, cervical, ovarian, breast and colon cancer.

 

·        D-dimer - Postoperative survival was significantly shorter in colorectal cancer patients with elevated preoperative d-dimer levels.  Evaluation of preoperative D-dimer level can be used to predict postoperative survival.

 

·         EGFR (epidermal growth factor receptor) Expression. This is a test to evaluate the probability of response to CPT-11 (irinotecan) therapy in colorectal cancer. In a study evaluating 8 different genes as predictive factors for first-line CPT-11-based chemotherapy in colorectal cancer patients, a high intratumoral gene expression level of EGFR was shown to be the most important factor in distinguishing responders from non-responders (1). In this study, the best cut-off point of EGFR expression was an EGFR/actin ratio of 1.58 x 10-3. EGFR was also reported to be one of the predictive factors for treatment of colorectal cancer patients with cetuximab/bevacizumab/irinotecan (2) 1. Vallbohmer et al. 2006. Int. J. Cancer 119:2435-2442. 2. Azuma et al. 2007 J Clin Oncol 25:18s (suppl; abs. 4113)

 

·        ERCC1 (excision repair cross-complementing factor 1) Gene Expression.  ERCC1 gene expression is a predictive marker for platinum therapy in many different types of cancer as well as colorectal cancer.  For patients with high ERCC1 levels, FOLFIRI (the combination of Folinic acid, 5-FU and irinotecan) may represent a better firstline treatment option than FOLFOX (the combination of Folinic acid, 5-FU and oxaliplatin). (Response Genetics web site)

 

·        Fibrinogen test – is another very relative test to access the likelihood of cancer developing or progressing.  It also is a good predictor of thrombosis risk and blood clots. Fibrinogen levels are best to keep below 350.

 

·        Folate and homocysteine - There is an increasing evidence, stemming from epidemiological studies as well as studies performed in human biopsies and animal and cell culture models, suggesting that folate is chemopreventive in colonic carcinogenesis. Hyperhomocysteinemia is frequently associated with folate deficiency. Having found that homocysteine enhances colon cancer cell growth while metabolites of folate inhibit cell proliferation, we investigated the effects of simultaneous treatment in colon cancer cells. RESULTS: Folate inhibited cell proliferation moderately within 24 h. Its metabolites, dihydrofolate and 5-MTHF (5- methyltetrahydrofolate is the most biologically active form of folic acid) were more potent inhibitors of cell growth. In homocysteine-treated cells, both folate and 5-MTHF reversed the homocysteine-induced enhancement of growth. In contrast, folate reduced the Caco-2 cell growth rate to control values and 5-MTHF depleted growth of homocysteine-treated cells to levels significantly lower than controls. CONCLUSIONS: Our data suggest that 5-MTHF, being the key metabolite in both the folate and homocysteine metabolic pathway, is the main modulator of growth-promoting actions of homocysteine as well as antiproliferative effects of folate in colon cancer cells. (Akoglu et al 2004)

 

·        HbA1c -- (Hemoglobin A1-C) – increased levels of this indicate impaired glycemic control.

 

·        HbA1c - Increasing HbA1c percentages were statistically significantly associated with a mild increase in colorectal cancer risk in the whole population.  In women, increasing HbA1c percentages were associated with a statistically significant increase in colorectal cancer risk and with a borderline statistically significant increase in rectum cancer. No significant association with cancer risk was observed in men. (Rinaldi et al 2008)

 

·        HIF-1 & 2 - Targeting both HIF-1* and HIF-2 in human colon cancer cells improves tumor response to sunitinib treatment. Disruption of HIF-1α, HIF-2α, or both HIF-1α and HIF-2α genes led to improved tumor response to sunitinib. (Dang et al 2009)  * HIF-1 is the major transcription factor that is specifically activated during hypoxia.  Active HIF-1 induces the expression of various genes whose products control angiogenesis, glucose metabolism, survival and tumor spread.  HIF-1 activates VEGF.  Hypoxia protects cancer cells from chemo-induced apoptosis by inducing the expression of AP-1.  HIF-1 controls the expression of multi-drug resistance-related genes mdrl, drug resistance P-glycoprotein and lung resistance protein.

 

·        Homocysteine levels let you know if you are methylating properly.  Mutations and methylation are linked to colon cancer.  That is one of the reasons why they propose green vegetables and folic acid to be preventative to colon cancer because those become methyl donors and they improve methylation and inhibit the acquired SNPs (single nucleotide polymorphisms) – which are just simply gene abnormalities that start to cause enough problems that cancer can be started.  Homocysteine should be less than 9.  If it is high it can mean you don not detoxify Xeloda well.

 

·        Homocysteine – is created when the body uses the amino acid, methionine, for methylation.  Methylation is an important reaction in the body, which leaves homocysteine as a by-product.  Normally homocysteine is converted back to methionine, or used to create cysteine and other useful substances.  If these conversions are blocked, however, homocysteine accumulates, which can lead to a host of negative reactions.  Abnormal metabolism and elevated blood levels of homocysteine create a condition that is highly toxic to both cellular and fibro-elastic components of the vascular wall.  Homocysteine can damage blood vessels and nerves, and has been linked to heart attacks, strokes, cancer (particularly colon, breast, and prostate), Alzheimer’s disease, osteoporosis and other neurological diseases, depression, birth defects, gout, cervical dysplasia, and rheumatoid arthritis.

 

·        Homocysteine – plasma homocysteine is a functional marker of folate status.  Elevated levels of homocysteine increase risk of heart attack, rheumatoid arthritis, cancer, etc.

 

·        Insulin-like Growth Factor-1 (IGF-1) – Recent studies of the interrelationship of IGF-1, insulin, and IGF-binding proteins indicate a possible correlation of increased bioavailability of IGF-1 with increased risk of colon cancer. Laboratory Tests and Diagnostic Procedures, p. 679 (2008)

 

·        IGF-1 – A positive correlation was found between dietary and lifestyle, plasma IGF-1, and colon cancer incidence rates.

 

·        Ki-67 – High levels predict lower chances of survival in colorectal cancer.

 

·        Ki-67 – The Ki-67 monoclonal antibody is used to determine the proliferation state of breast cancer, bone cancer, brain tumors, cervical cancer, colorectal cancer, endometrial cancer, liver tumors, lymphomas.  Laboratory Tests and Diagnostic Procedures, pp.689-690  (2008)

 

·        KRAS (K-ras gene) Mutation Analysis.  All studies to date indicate that KRAS mutation is highly predictive of a non-response to cetuximab or panitumumab.  Colorectal cancer patients with mutated KRAS should consider foregoing treatment with EGFR inhibitors. (Response Genetics web site)

 

·        LDH-5 -  Lactate dehydrogenase 5 – regulates, under hypoxic conditions, the anaerobic transformation of pyruvate to lactate for energy acquisition.  Several studies have shown that serum LDH may be an ominous prognostic marker in malignant tumors.  LDH-5 and pKDR (the phosphorylated (activated) form of Kinase insert Domain-containing Receptor) provide important prognostic information in operable colorectal cancer.  The strong association between LDH-5 and pKDR expression would justify their use as surrogate markers to screen patients for tyrosine kinase inhibitor activity.

Glycolysis shows if cancer cells are replicating and it is showing as active cancer.  Cutting back on sugar is a great thing. (Donnie 8-7-09)

 

·        LDHA - There is a significant correlation between the intratumoral gene expression of LDHA (lactate dehydrogenase A), HIF1 alpha, HIF2 alpha, Glut 1*, NRP1 (neuropilin 1), VEGFA and VEGFR1. Patients with high serum LDH have increased intratumoral gene expression of VEGFA and VEGFR1.  The results also support the hypothesis that serum LDH levels may serve as a surrogate marker for activation of the HIF-related genes in the tumor of metastatic colorectal cancer patients. (Azuma, 2007)

*Glut-1 gene is a potential hypoxic marker in colorectal cancer.  (Fu Yen Chung et al 2009)

  LDH-5 signifies high VEGF levels. (Donnie 6-12-09)

 

·        Leptin - These data showed, for the first time, that leptin promotes colon cancer HT29 cell survival upon butyrate challenge by counteracting the apoptotic programs initiated by this short chain fatty acid probably through NF-kappaB pathways. Although further studies are required to unravel the precise mechanisms, these data may have a significance in the pathogenesis of colorectal cancer and ulcerative colitis diseases. (Rouet-Benzineb et al 2004)

 

·        Leptin and VEGF - Both leptin (a hormone produced by fat cells) and VEGF (vascular endothelial growth factor) are growth and angiogenic cytokines that are upregulated in different types of cancer and have been implicated in neoplastic progression. Here we investigated the molecular mechanism by which leptin and VEGF expression are regulated in colon cancer by epidermal growth factor (EGF). In colon cancer cell line HT-29, EGF induced the binding of signal transducer and activator transcription 3 (STAT3) to STAT3 consensus motifs within the VEGF and leptin promoters and stimulated leptin and VEGF mRNA and protein synthesis. All these EGF effects were significantly blocked when HT-29 cells were treated with an inhibitor of the phosphoinositide 3-kinase (PI3K) pathway, LY294002, or with small interfering RNA (siRNA) targeting STAT3. Thus, our study identified the EGF/PI3K/STAT3 signaling as an essential pathway regulating VEGF and leptin expression in EGF-responsive colon cancer cells. This suggests that STAT3 pathways might constitute attractive pharmaceutical targets in colon cancer patients where anti-EGF receptor drugs are ineffective. (Cascio et al 2009)

 

·        NF-κB - Positive expression of NF-kB was found in 72 (73.5%) colorectal cancer cases, whereas COX-2 expression was found in 48 (49.0%) cases. (Abdulla 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-{kappa}B (NF;κB).  (Pan et al., 2002)

 

·        p53 - Mutation of the p53 tumor suppressor gene is the most common genetic alteration in human cancer. The highest frequency of p53 mutations reported in human cancers are lung, 56%; colon, 50%.

 

·        p53 – The detection of mutations in tumor-suppressor genes is associated with approximately half of human cancers, including colorectal, breast, bladder, esophageal, liver, lung, ovarian and brain (p53) and pancreas cancers; leukemias; and male germ cell cancers (DCC). Laboratory Tests and Diagnostic Procedures, p. 361 (2008)

 

·        PAI-1 – Plasminogen activator inhibitor-1 -- the marker with the highest accuracy for colorectal cancer. A very good marker to run in case of colon cancer. High levels of PAI-1 were found associated with poor prognosis and low levels with good prognosis in colorectal cancer. Veripath tests for PAI-1.

 

·        PTEN - Patients with PTEN (phosphatase and tensin homologue) positive metastases and KRAS wild type had longer progression-free survival compared with other patients. PTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN immunohistochemistry and KRAS mutational analyses could help to identify a subgroup of patients with metastatic colorectal cancer who have higher chances of benefiting from EGFR inhibition. (Loupakis et al, 2009)

·        Thymidylate synthetase catalyses the methylation of dUMP to dTMP. As the sole de novo source of thymidylate in the cell, it is an important target for drugs such as 5-fluorouracil and methotrexate. Over-expression of thymidylate synthetase has been linked to drug resistance. For example, in 48 patients who received fluorouracil based therapy for metastatic colorectal cancer, patients with high TS expression had a median survival time of 15.4 months, compared to 18.4 months for patients with low TS expression (p=0.02) (PharmGKB.org website)

·        TS (thymidylate synthetase) Gene Expression. Since its introduction 50 years ago, 5-fluorouracil (5-FU) has been a mainstay of chemotherapy of colorectal cancer.  Because of the modest overall response rate to 5-FU as a single agent (ca. 15-20%), much research has been directed at identifying predictive molecular markers of tumor sensitivity or resistance. Many studies agree that high levels of TS predict for resistance of tumors to 5-FU and its derivatives, even with combination chemotherapy regimens. (Response Genetics web site) (Cohen et al, 2003)

 

·        VEGF (vascular endothelial growth factor) – Increased levels of VEGF have been associated with many forms of cancers.  When secreted, VEGF acts directly on endothelial cells to induce development of tiny blood vessels (angiogenesis) which helps provide the blood flow and nourishment necessary to enable continued growth of the tumor.  Because of its role in stimulating angiogenesis near tumors, VEGF is also thought to be an important factor in allowing metastasis to occur.  Platelet count and VEGF levels are normally positively correlated.  Thus VEGF levels must be corrected when platelets are elevated.  Recently, bevacizumab has been approved as an anti-VEGF therapy for metastatic colorectal carcinoma. Laboratory Tests and Diagnostic Procedures, p. 115 ( 2008)

 

·        VEGF - Normal human colonic microvascular endothelial cells (HUCMEC) produce vascular endothelial growth factor (VEGF) and express the receptors, kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase, through which VEGF mediates its actions in the endothelium. VEGF induces the tyrosine phosphorylation of KDR and a proliferative response from HUCMEC comparable to that elicited from human umbilical vein endothelial cells (HUVEC). (D Wang et al 2002)

 

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-{kappa}B (NF;κB).  (Pan et al., 2002)

 

·        Vitamin D – Patients with the highest levels of vitamin D were 48% less likely to die from any cause – including colon cancer – than those who had the lowest levels of vitamin D.  Higher prediagnosis levels of Vitamin D after a diagnosis of colorectal cancer may significantly improve overall survival. (Ng K & Fuchs C, et al 2008)

 

·        Vitamin D - Raising Vitamin D levels may prevent up to half of all breast and two thirds of colorectal cancer cases in the US.  The investigators recommend a daily intake of 2000 IU of Vit. D3 and when possible moderate sun exposure.

 

·        Zinc - In this study (1), zinc intake had a clear inverse association with both proximal and distal colon cancers. (Duk-Hee Lee et al 2005)   

By bringing zinc up it will bring copper down.  (Donnie  8-7-09)

 

Actions of Cancer Preventive Botanicals & Nutrients on Selected Cancer Targets

COX -2

·        Cyclooxygenase-2 (COX-2) is over-expressed in colorectal cancer (CRC), rendering tumour cells resistant to apoptosis. Selective COX-2 inhibition is effective in CRC prevention, although having adverse cardiovascular effects, thus focus has shifted to downstream pathways. (Doherty et al 2009)

 

·        COX-2 may be a relevant target for prevention and/or treatment of colorectal cancer as well as many other types of cancer.

 

·        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

o       Baicalein, from Chinese skullcap (ICII >95%)

o       Curcumin

o       EPA/DHA in n-3 fatty acids from fish oils

o       Pterostilbene

o       Quercetin

o       Resveratrol

o       Salicin (Corydalis 30%) Willow bark extract (WBE)

o       Trans-resveratrol

o       Willow Bark Extract (WBE) inhibits the cell growth and promotes apoptosis in human colon and lung cancer both through COX-selectivity and nonCOX-2. Other synergistic compounds with WBE include other salicyl alcohol derivates, flavonoids, proanthocyanidins.

 

·        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).

 

·        Naturally occurring COX-2 inhibitors such as curcumin and certain phytosterols have been proven to be effective as chemopreventive agents against colon carcinogenesis with minimal gastrointestinal toxicity.

 

EGFR

·        EGFR – epidermal growth factor receptor - participates in cellular signaling pathways.  It is expressed in many human tumor types, including colorectal cancer. (Zhang 2005)

 

·        Gene polymorphisms active in the EGFR pathway may be associated with the sensitivity of colorectal cancer patients to platinum-based chemotherapy.

 

·        Patients with PTEN-positive metastases and KRAS wild type had longer progression-free survival compared with other patients.  PTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan.  The combination of PTEN IHC and KRAS mutational analysis could help to identify a subgroup of patients with metastatic colorectal cancer who have higher chances of benefiting from EGFR inhibition. (Loupakis 2009)

 

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

 

NF-κB (Nuclear Factor Kappa B)

·        Positive expression of NF-kB was found in 72 (73.5%) colorectal cancer cases, whereas COX-2 expression was found in 48 (49.0%) cases. (Abdulla 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)

 

·        One study demonstrated an association between VEGF expression, p53 status and angiogenesis, suggesting that mutant p53 plays a central role in promoting angiogenesis in colon cancer progression. (Faviana et al 2002)

 

·        p53 and VEGF were expressed in colorectal cancer (CRC) and had a predictive power of aggressive clinical behaviour in CRC. (Weekes et al 2009)

 

·         Researchers found that diets with a high glycemic load as well as diets high in red meat, fast food and trans-fatty acids may play an important role in the process of the p53 mutation that causes colon cancer. (Slattery et al 2002)

 

·        Natural compounds that normalize p53

o       6-Gingerol

o       Curucumin

o       EGCG

o       Folate, Tocotrienols and Vit E succinate

o       OPCs

o       Oridonin (Rabdosia)

o       Paw paw seed

o       Quercetin

o       Resveratrol

o       Withanone (Ashwagandha extract)

 

VEGF 

·        p53 and VEGF were expressed in colorectal cancer (CRC) and had a predictive power of aggressive clinical behaviour in CRC. (Weekes et al 2009)

 

·        Increased levels of VEGF have been associated with many forms of cancers.  When secreted, VEGF acts directly on endothelial cells to induce development of tiny blood vessels (angiogenesis) which helps provide the blood flow and nourishment necessary to enable continued growth of the tumor.  Because of its role in stimulating angiogenesis near tumors, VEGF is also thought to be an important factor in allowing metastasis to occur.  Platelet count and VEGF levels are normally positively correlated.  Thus VEGF levels must be corrected when platelets are elevated.  Recently, bevacizumab has been approved as an anti-VEGF therapy for metastatic colorectal carcinoma. Laboratory Tests and Diagnostic Procedures, p. 115 ( 2008)

 

·        Herbs and Compounds that Inhibit VEGF

o       Angelica sinensis (dong quai) – 4-hydroxzyderricin

o       Artemisia annua (Chinese wormwood) – 95% artemisinin and other related terpenes and flavonoids

o       Camellia sinensis (green tea extract) -50% EGCG, plus other compounds

o       Coriolus versocolor – 15% polysaccharides

o       Curcuma longa (turmeric) – 95% curcumin

o       Ginkgo biloba – 27% Flavones and 7% terpenes

o       Magnolia seed cones – 90% honokiol

o       Ocimum spp. (Basil) Ursolic acid

o       Polygonum cuspidatum (Japanese knotweed) – 20% resveratrol

o       Rabdosia rubescens (Rabdosia)

o       Scutellaria baicalensis (Chinese Baical skullcap) – 95% baicalin and other compounds, mostly flavonoids

o       Silybum marianum (milk thistle) – 80% Silymarin

o       Taxus breviflora (Pacific yew) – taxol and other related taxins

o       Viscum album (Mistletoe)

o       Vitus vinifera (grape seed extract) – 95% OPCs

 

Colon Cancer-preventive and/or Suppressive Botanicals and Nutrients

·        Andrographolide

·        Anthocyanins

·        Boswellic acid

·        Coriolus versicolor extract

·        Curcumin

·         Folate

·        Green Tea Extract

·        High dose antioxidants and fish oil

·        Honokiol

·        Olive oil

·        Omega-3 polyunsaturated fatty acids

·        Paw Paw seeds (acetogenins

·        Pterostilbene

·        Red yeast rice

·        Resveratrol

·        Riboflavin

·        Rosemarinic acid

·        Scutellaria (wogonin)

·        Selenium

·        Sulforaphane

 

Studies Supporting the Use of These Botanicals in Colon Cancer

·        Acetogenins have shown highly potent cytotoxicities with notable selectivity for the HT-29 human colon cancer cell line.

 

·        Andrographolide -- derivative Compound 2 was found to be selective towards leukemia and colon cancer cells and Compound 4 was selective towards leukemia, ovarian and renal cancer cells. (Compounds 2 and 4 were screened at the US National Cancer Institute)

 

·        Anthocyanins – are the antioxidant pigments from a range of fruit and vegetables.  Researchers found that anthocyanins from purple corn were must potent in inhibiting the growth of colon cancer cells, followed by chokeberry and bilberry, then by purple carrots and grape.

 

·        Boswellic acid – as AKBA (acetyl-beta-boswellic acid) inhibited cellular growth in several colon cancer cell lines.  The growth inhibitory effect of AKBA was dependent on p21 but not p53.

 

·        Boswellic acids -- particularly AK-BA and K-BA have antiproliferative and apoptotic effects in colon cancer HT-29 cells

 

·        Combinations - We report here the efficacy of dietary antioxidants in combination with chemotherapy on tumor growth in the orthotopic COLO-205-green fluorescent protein (GFP) human colon cancer mouse model. The results of the present study therefore indicate enhancement of cisplatin efficacy by high-dose antioxidants in combination with fish oil for colon cancer progression and suggests the design of clinical trials for this regimen. (Ma H, et al 2009)

 

·        Coriolus versicolor extract (CVE) significantly extended survival at five years or beyond in cancers of the stomach, colon-rectum, esophagus, nasopharynx and lung (non-small cell types), and in HLA B40-positive breast cancer subset.

 

·        Curcumin - Naturally occurring COX-2 inhibitors such as curcumin and certain phytosterols have been proven to be effective as chemopreventive agents against colon carcinogenesis with minimal gastrointestinal toxicity.

 

·        Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating the EGFR and IGF-1R signaling pathways.  The inclusion of curcumin to the conventional chemotherapeutic agent(s)/regimen could be an effective therapeutic strategy for colorectal cancer. (Patel BB et al 2008)

 

·        Curcumin has been shown to inhibit MAPK and NF-κB, which caused a dose-dependent induction of apoptosis (cell suicide) in human colon cancer cells.

 

·        Curcumin inhibits the production of proinflammatory cytokines by tumor cells, including IL-6 and 8.

 

·        Curcumin treatment causes p53 and p21-independent G2/M phase arrest and apoptosis in HCT-116(p53+/+), HCT-116(p53-/-) and HVT-116(p21-/-) cell lines in colon cancer.

 

·        Folate – has a protective effect against colon cancer.  Avoid alcohol as alcohol mitigates the protective effect of folate.

 

·        Green Tea Extract – is an effective supplement for the chemoprevention of metachronous colorectal adenomas. (Shimizu et al 2008)

 

·        Honokiol -- induces apoptosis through p53-independent pathway in human colorectal cell line RKO.

 

·        Isothiocyanates - Histone deacetylase (HDAC) inhibitors reactivate epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis.  Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic. Broccoli sprouts are a rich source of sulforaphane, an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits histone deacetylase activity in human colon, prostate, and breast cancer cells. (Nian et al 2009)

 

·        Olive oil -- contains a high amount of omega-9 fatty acids and important polyphenols which have been shown to inhibit colon cancer.

 

·        Omega-3 fatty acid (omega-3 FA) consumption has long been associated with a lower incidence of colon, breast and prostate cancers in many human populations. Human trials have demonstrated omega-3 FA to have profound anti-inflammatory effects in those with cancer. In vitro and small animal studies have yielded a strong body of evidence establishing omega-3 FA as having anti-inflammatory, anti-apoptotic, anti-proliferative and anti-angiogenic effects. The conclusions drawn from this review suggest that omega-3 FAs in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found principally in oily fish have potent anti-angiogenic effects inhibiting production of many important angiogenic mediators namely; Vascular Endothelial Growth Factor (VEGF), Platelet-Derived Growth Factor (PDGF), Platelet-Derived Endothelial Cell Growth Factor (PDECGF), cyclo-oxygenase 2 (COX-2), prostaglandin-E2 (PGE2), nitric oxide, Nuclear Factor Kappa Beta (NFκB), matrix metalloproteinases and beta-catenin. (Spencer et al 2009)

 

·        Omega-3 PUFAs - Consumption of omega-3 polyunsaturated fatty acids was associated with a 37% reduction of colorectal cancer risk.

 

·        Omega-3 PUFAs - This study was designed to examine the effects of a diet rich in omega-3-polyunsatruated fatty acids on a model of colorectal metastasis. It was found that the omega-3-polyunsaturated fatty acids from fish oil appear to decrease malignant metastatic tumor growth in the liver. (Gutt et al, 2007)

 

·        Paw paw seeds - Two new bioactive mono-tetrahydrofuran (THF) gamma-lactone acetogenins, –asitrilobins C (1) and D (2), were isolated from the seeds of paw paw.  Compounds 1 and 2 showed selective cytotoxicity comparable with adriamycin for the breast carcinoma (MCF-7) and the colon adencarcinoma (HT-29) cell lines.

 

·        Pterostilbene, an active constituent of blueberries, inhibits colon cancer in animals.

 

·        Red yeast rice inhibited both tumor cell growths and enhanced apoptosis in HCT-116 cells. These results suggest that the matrix effects of red yeast rice beyond monacolin K alone may be active in inhibiting colon cancer growth. Red yeast rice with or without monacolin K may be a botanical approach to colon cancer chemoprevention worthy of further investigation. (Becker et al 2008)

 

·         Resveratrol and pterostilbene Epidemiological studies have linked the consumption of fruits and vegetables to a reduced risk of colon cancer, and small fruits are particularly rich sources of many active photochemical stilbenes, such as resveratrol and pterostilbene. (Rimando and Suh 2008)

 

·        Riboflavin – reduces the risk of colon cancer.  Riboflavin, as FAD, is a cofactor for MTHFR and there is evidently some interaction among riboflavin status, folate status and genotype in determining plasma homocysteine, a functional marker of folate status.

 

·        Rosmarinic acid - (in holy basil and rosemary) has been shown to down-regulate COX-2 and suppress colon cancer.

 

·        Selenium - High levels of serum selenium and reported folate jointly were associated with a substantially reduced risk of colon cancer. Folate status should be taken into account when evaluating the relation between selenium and colon cancer in future studies. Importantly, weight loss, stage at diagnosis, or time from diagnosis to blood draw did not appear to produce strong bias in our study.  (Connelly-Frost, et al 2009)

 

·        Selenium - Low selenium status has been associated with increased risk of colorectal cancer.

 

·         Sulforaphane - Despite the reported cytotoxicity and apoptosis-inducing properties of sulforaphane (SF) in colon cancer cells, the details concerning individual mechanisms and signaling cascades underlying SF-mediated apoptosis remain unclear.  Our results indicate that in SW620 cells SF acts to induce multivariate cascades including DNA-damage response pathway whose proapoptotic signaling is nevertheless reduced owing to the mutant status of p53 and caspase-2-JNK pathway which seems to complement and enhance p53-dependent signaling, however only in wild-type p53. Furthermore, both pathways require the active role of mitochondria and do not depend on generation of ROS, making SF an attractive chemopreventive agent whose antitumor properties should be further investigated in colon cancer. (Rudolf et al 2009)

 

·        Wogonin, from Chinese Scutellaria, was shown to induce apoptosis in human prostate and colon carcinoma cell lines by enhancing expression of tumor suppressing protein p53, and consequently enhancing expression of the p53 target-genes p21, p27 and PUMA.  (Lee DH et al 2008)

 

Other Considerations

·        Toxic and potentially carcinogenic substances are frequently metabolized and conjugated in the liver before being excreted via bile into the small intestine.  These compounds pass into the colon, where bacterial enzymes act to hydrolyze the conjugates and release the parent toxic compound into the colonic lumen.  The presence and activity of these enzymes are lowest among lactic acid bacteria (lactobacilli and bifidobacteria). Thus – it has been suggested that by increasing levels of lactobacilli and bifidobacteria in the colon and decreasing the levels of other species a corresponding decrease in the production of carcinogenic compounds would occur.  Studies in rodents suggested that continual consumption is necessary for the effect.  (Phytopharmaceuticals in Cancer Chemoprevention, pages 630-631)

 

·        Yogurt – Researchers have found that the dialyzate fraction of yogurt possesses anti-tumor activity.  Lactobacilli and bifidobacteria found in yogurt produce compounds within the colon that increase beta glucaronization and nitroreductase, which help the body to excrete carcinogens and hormones more efficiently. 

 

·        Diets high in red and processed meat have been shown to increase risk of colorectal cancer, whereas diets rich in fruits, vegetables and fiber lower colorectal cancer risk.

 

·        Calcium intake consistent with current recommendations is associated with a lower risk of total cancer in women and cancers of the digestive system, especially colorectal cancer, in both men and women.

 

References

Books

  1. Bagachi, Debasis & Harry G. Preuss, Phytopharmaceuticals in Cancer Chemoprevention, CRC Press, Boca Raton, 2005

 

  1. Boik, John, Natural Compounds in Cancer Therapy, Oregon Medical Press, Princeton, MN, 2001

 

  1. Boik, John, Cancer & Natural Medicine, A Textbook of Basic Science and Clinical Research, Oregon Medical Press, Princeton, MN, 1996

 

  1. Chernecky, Cynthia C, and Barbara J. Berger, Laboratory Tests and Diagnostic Procedures, Saunders, St. Louis, 2008

    5.   Heber, David, Nutritional Oncology, Academic Press, London, 2006

    6.   Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999

 

Monographs

  1. Yance, Donald, “A Novel Approach to Cancer Treatment”, Medicines from the Earth 2005, Official Proceedings, June 4th to June 6th, 2005, pages 189-213, Herbal Educational Services, Ashland, OR, 2005

 

  1. Yance, Donald, “A Revolutionary Approach to Weight Management”,  Medicines from the Earth 2006, Official Proceedings, June 2 through June 5, 2006, pages 154-168, Herbal Educational Services, Ashland, OR, 2006

 

  1. Yance, Donald, “Andrographis (Andrographis paniculata)” (Monograph) 2008
  2. Yance, Donald, “Astragalus root (Astragalus membranasceus)” (Monograph) 2009

 

  1. Yance, Donald, “Boswellia serrata (Indian Frankincense)” (Monograph) 2009
  2. Yance, Donald, “Botanical Compounds for Cancer-Related Pain”,  Medicines from the Earth 2006, Official Proceedings, June 2 through June 5, 2006, pages 169-190, Herbal Educational Services, Ashland, OR, 2006

 

  1. Yance, Donald, “Cancer and Inflammation”, Medicines from the Earth, Official Proceedings, May 29-June 1, 2009, pages 132-140, Herbal Educational Services, Ashland, OR, 2009

 

  1. Yance, Donald, “Cancer and Inflammation: The emerging role of botanical compounds in targeting proinflammatory pathways, with particular attention to the NF-κB signaling pathway” (Monograph) 2009

 

  1. Yance, Donald, “Carnitine” (Monograph) 2009
  2. Yance, Donald, “Cat’s claw (Uncaria tomentosa) Uno de gato” (Monograph) 2009

 

  1. Yance, Donald, “Cholesterol, Statins and the Truth about Cardiovascular Health and Disease”, (Monograph)  2009

 

  1. Yance, Donald, “Cholesterol, Statins, and the Truth about Cardiovascular Health”, Medicines from the Earth 2005, Official Proceedings, June 4th to June 6th, 2005, pages 165-188, Herbal Educational Services, Ashland, OR, 2005

 

  1. Yance, Donald, “Copper Antagonists Inhibit Angiogenesis” (Monograph) 2009
  2. Yance, Donald, “Donald Yance’s Eclectic Triphasic Medical System (ETMS): An Integrative Wholistic Approach to Treating and Preventing Cancer”, (Monograph) 2009

 

  1. Yance, Donald, “EPA and DHA rich fish oil” (Monograph) 2009
  2. Yance, Donald, “Feverfew” (Monograph) 2008
  3. Yance, Donald, “Ginger” (Monograph) 2008
  4. Yance, Donald, “Grape (Vitis vinifera) & Japanese Knotweed (Polygonum cuspidatum)” (Monograph) 2009

 

  1. Yance, Donald, “Green Tea” (Monograph) 2008
  2. Yance, Donald, “Hyper-coagulation and Cancer” (Monograph) 2009
  3. Yance, Donald, “Insulin Resistance” (Monograph) 2004
  4. Yance, Donald, “Korean ‘Asian’ Ginseng & American Ginseng” (Monograph) 2009

 

  1. Yance, Donald, “L-Arginine” (Monograph) 2009
  2. Yance, Donald, “Licorice” (Monograph) 2009
  3. Yance, Donald, “Magnolia bark” (Monograph) 2009
  4. Yance, Donald, “Milk Thistle” (Monograph) 2009
  5. Yance, Donald, “Natural Compounds that modulate the Bcl-2 Protein” (Monograph) 2008

 

  1. Yance, Donald, “Osteoporosis, Nutrition, and Botanical: Myths, Perceptions, Truths and Natural Solutions”, Medicines from the Earth, Official Proceedings, May 29-June 1, 2009, pages 141-149, Herbal Educational Services, Ashland, OR, 2009

 

  1. Yance, Donald, “Prostate Cancer, A Revolutionary Wholistic Approach.  Applications for Botanical and Nutritional Medicine”, (Monograph) 2009

 

  1. Yance, Donald, “Pterocarpus marsupium” (Monograph) 2009

 

  1. Yance, Donald, “Quercetin” (Monograph) 2009
  2. Yance, Donald, “Rhaponticum carthamoides”, Journal of the American Herbalists Guild, Fall/Winter 2004 (Vol. 5, No.2)

 

  1. Yance, Donald, “Selenium” (Monograph) 2009
  2. Yance, Donald, “Skullcap, Chinese” (Monograph) 2009
  3. Yance, Donald, “Sulforaphane glucosinolate (SGC)” (Monograph) 2005
  4. Yance, Donald, “The p53 suppressor gene” (Monograph) 2009
  5. Yance, Donald, “Turmeric” (Monograph) 2009

Online

  1. PubMed, http://www.ncbi.nlm.nih.gov/pubmed/

 

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