Understanding Colon Cancer

compiled by John G. Connor, M.Ac., L.Ac. edited by Barbara Connor, M.Ac., L.Ac. 

Table of Contents
Introduction
Background to Colorectal Cancer
Examples of Botanicals and Nutrients that May be Preventive or Suppressive in Colon Cancer Cell Lines
Research on the Use of these Botanicals and Nutrients in Colon Cancer Cell Lines
References

Introduction
Colorectal cancer (CRC) represents the third most common cancer worldwide, second only to lung cancer and gastric cancer. Furthermore, it is estimated that there are more than 370,000 cases of colon and rectal cancer diagnosed in Europe every year, with 200,000 cases resulting in death. (Bai et al 2012)

Colorectal cancer is the fourth leading cause of new cancer cases diagnosed in the United States and is the second leading cause of cancer death. (Modiri et al 2013)About 3–5% of all CRCs are due to inherited genetic defects and up to 25% of patients may have some degree of familiality for this disease, but the majority of CRCs occur in a sporadic manner in the absence of a documented family history. (Link et al 2013)

Colorectal cancer results from the accumulation of both acquired genetic and epigenetic changes that transform normal glandular epithelium into invasive adenocarcinomas. There are multiple molecular pathways to colon cancer, and these pathways involve both mutations and epigenetic alterations. (Lao et al 2011)

Colorectal cancer progresses through multiple distinct stages in its evolution. Morphologically, inappropriate proliferation and antiapoptosis cause formation of adenomas, which evolve into preinvasive carcinoma in situ. Then, preinvasive CRCs acquire the ability to invade through the submucosa and muscularis, metastasize, and survive outside the colon microenvironment niche. Mechanistically, mutations activating WNT signaling in transformed colon cancer cells are an early event. Subsequently, mutations in KRAS, TGFBR1, BRAF, TP53, DNA mismatch repair genes, FBXW7, NOTCH, PI3 kinase, and other signaling pathways accumulate to promote CRC tumor progression to invasive and metastatic disease. (Chen et al 2012) 

As 5-year survival for early-stage CRC is approximately 90% compared with 15% for metastatic CRC, understanding in great detail the mechanisms that regulate the transition from indolent (adenomas and carcinoma in situ) to locally invasive early clinical stage (stage I/II) and metastatic later stage (stage III/IV) CRC is critical to improving patient outcomes. (Chen et al 2012) 

Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by luminal cytotoxicity and reactive oxygen species. This surface injury is overcompensated by hyperproliferation and hyperplasia of crypt cells. Transcriptome analysis of mucosa of heme-fed mice showed, besides stress- and proliferation-related genes, many upregulated lipid metabolism-related PPARα target genes. (Ijessennagger et al 2012)

Targeted Therapies Approach to Cancer
Systemic therapy has led to a median survival time for patients with advanced colorectal cancer almost fourfold longer than that expected with best supportive care, an outcome achieved through combining chemotherapeutic and targeted biologic agents. (Blanke et al 2011)

Conventional chemotherapy, although directed toward certainmacromolecules or enzymes, typically does not discriminate effectivelybetween rapidly dividing normal cells (e.g., bone marrow andgastrointestinal tract) and tumor cells, thus leading to severaltoxic side effects. Tumor responses from cytotoxic chemotherapyare usually partial, brief, and unpredictable. In contrast,targeted therapies interfere with molecular targets that havea role in tumor growth or progression. These targets are usuallylocated in tumor cells, although some like the antiangiogenicagents 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 chemotherapyor radiation to produce additive or synergistic anticancer activitybecause their toxicity profiles often do not overlap with traditionalcytotoxic chemotherapy. Thus, targeted therapies represent anew and promising approach to cancer therapy, one that is alreadyleading to beneficial clinical effects. There are multiple types of targeted therapies available, includingmonoclonal antibodies, inhibitors of tyrosine kinases, and antisenseinhibitors of growth factor receptors. (Arora and Scholar, 2005)

We need to be thinking about targeting a biological network, not just a single molecule.  Any time you put pressure on cells and their dynamic signaling networks, you are inevitably challenging them to get around the problem they are experiencing.  We need to be smart up front and know how these cells will respond to a drug challenge, and the dominant resistance mechanisms.  (Louis Weiner, MD, Director, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center. Sept. 2010) 

Background to Colorectal Cancer

Standard chemotherapies in advanced colorectal cancer (CRC) patients have evolved from simple fluorouracil (FU)-based treatment to FU-folinic modulation, FU combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), and finally to associations of FU-containing chemotherapies with biological targeted therapies. The wide range of treatment options creates a need for individual predictive factors in order to choose the optimal treatment for a given patient. To this end, tumour molecular markers constitute a valuable approach. (Etienne-Grimaldi et al 2010)

Currently, the approved agents for treatment of CRC include monoclonal antibodies or small molecule tyrosine kinase inhibitors against the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways, as well as the standard chemotherapeutic agents 5-FU, irinotecan, and oxaliplatin. (Pitts et al 2013)

The standard adjuvant treatment of stage III and high-risk stage II colon cancer is to administer 6 months of oxaliplatin- and fluorouracil-containing chemotherapy. However, nearly a third of stage III patients still recur. The positive results of cetuximab and bevacizumab added to chemotherapy in patients with metastatic colorectal cancer formed the basis to explore the role of these agents in the adjuvant setting. However, two adjuvant trials with bevacizumab and one adjuvant trial with cetuximab have failed to show any benefit of adding these agents to standard chemotherapy. (Oyan B 2012)

5-Fluorouracil (5-FU) is one of the most common and effective clinical chemotherapy medications for treatment of digestive tract tumors, with a specific set of effects. Internally, 5-FU not only transforms into corresponding nucleotides and helps develop an anti-tumor effect, it can also induce apoptosis. Theoretically, 5-FU can bring about carcinogenic cell DNA deterioration and acceleration of tumor cell apoptosis. Whereas 5-FU only had a single effective rate of 24%, and approximately 31% as the first-line drug of clinic chemotherapy on colon cancer, the increase in dosage could cause severe toxic- and side-effects, and gradually increasing drug resistance also limited its dosage and therapeutic effect. (Zhang et al 2013)

COX-2 – Higher cyclooxygenase 2 (COX-2) expression is often observed in aggressive colorectal cancers (CRCs). The findings of this study point to a potential benefit of combining COX-2 inhibitors with current regimens to achieve better response in the treatment of therapy-refractory CRC and in using COX-2 expression as a prognostic marker to help identify individuals who would benefit the greatest from closer follow-up and more aggressive therapy. (Rahman et al 2012)

Osteopontin (OPN) is a phosphoglycoprotein which is originally isolated from mineralized bone matrix, also is frequently secreted by different types of cancer cells, essential for growth and metastasis of breast, prostate, hepatic, melanoma, and other tumors. OPN signals through cell adhesion molecules, such as integrins and CD44. Gene-profiling studies have identified a correlation between advanced and metastatic colorectal tumors and high expression of OPN. A major influence of OPN on metastatic potential is through cellular attachment and migration across extracellular matrix proteins. OPN plays a significant role in colorectal cancer metastasis to liver through interaction with its receptors in hepatocytes, decreased homotypic adhesion, and enhanced heterotypic adhesion. (Huang et al 2012)

Examples of Botanicals and Nutrients that May be Preventive and/or Suppressive in Colon Cancer Cell Lines

Andrographolide 
Anthocyanins
Arginine
Astragalus
Berberine
Boswellic acid 
Conjugated linoleic acid
Curcumin 
Echinacea
EGCG
Folate 
Green Tea Extract 
High dose antioxidants and fish oil 
Inositol hexaphosphate (IP6)
Isothiocyanates
Modified citrus pectin (MCP)
Olive oil
Omega-3 polyunsaturated fatty acids 
Panax notoginseng
Pterostilbene 
Resveratrol
Rosemarinic acid 
Scutellaria (wogonin) 
Selenium 
Sulforaphane 
Ursolic acid

Studies Supporting the Use of These Botanicals & Nutrients in Colon Cancer
Epidemiological studies have suggested that herbal medicines and fruit extracts play a major role in the prevention and treatment of many types of cancer including that of the colon. (Law et al 2012) 

Andrographolide — a similar inhibitory effect of andrographolide on the invasion and MMP2 activity of the human colon cancer cell line HT29 was also observed. In summary, our results indicate that andrographolide exhibits anti-invasive activity against colon cancer cells via inhibition of MMP2 activity. (Chao et al 2010)

Anthocyanins (ACs) – are provided in the diet by foods such as strawberries, raspberries, and blackberries. Consumption of 100 g of berries would provide up to 500 mg of anthocyanins. We recently demonstrated that whole black raspberries powder, administered orally on a daily basis for an average of approximately 4 wk, led to the protective modulation of multiple epigenetic and cellular biomarkers in human colorectal tumors. our results suggest that ACs are responsible, at least in part, for the demethylation effects of whole black raspberries in colorectal cancers. (Wang et al 2013)

Antioxidants and fish oil – 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 et al 2009)

Arginine – Results showed that the MMP-2, MMP-9 and VEGF receptor levels in tumors were significantly lower, whereas tumor NO levels and spleen natural killer (NK) cell activities were higher in the Arg group than in the control group. These results were consistent with the in vitro study that dietary Arg supplementation inhibits the progression of colon cancer possibly by increasing NO secretion and consequently enhancing NK cell activity. (Yeh et al 2010)

Astragalus – Taken together, these findings suggest that Radix Astragali exerts anti-carcinogenic activity in colon cancer cells through modulation of mTOR signaling and downregulation of COX-2, which together reduce VEGF levels in tumor cells that could potentially suppress angiogenesis. (Law et al 2012)

Berberine enhances Cbl activity, resulting in down-regulation of EGFR expression and inhibition of proliferation in colon tumor cells. (Wang et al 2013)

Boswellic acid –  We previously reported that boswellic acids induced apoptosis in both colon and liver cancer cells by a pathway dependent on caspase-8 and caspase-3 activation but independent of Fas/Fas ligand interaction. In the present investigation, we examined whether the apoptotic effects of acetyl-11-keto-β boswellic acid (AKBA) in colon cancer cells can be modified by inhibition of the PI3K pathway. Conclusion: AKBA may activate the PI3K/Akt pathway and inhibition of the PI3K pathway significantly enhances AKBA-induced apoptosis. (Liu & Duan 2009) 

Conjugated linoleic acid (CLA) – was shown to elicit cancer protection in a variety of experimental carcinogenesis models, including that of colon cancer.  We reported previously that dietary CLA reduces tumor incidence in the colon of 1,2-dimethylhydrazine-treated rats. In addition, our in vitro study showed that CLA inhibits the G1→S cell cycle progression in HT-29 human colon cancer cells by inducing p21CIP1/WAF1. We also observed that t10c12 inhibits the growth of HT-29 and Caco-2 human colon cancer cells, whereas c9t11 had no effect on the growth. The results of this study indicate that t10c12 exerts its growth inhibitory effects in colon cancer cells through the induction of G1 cell cycle arrest. (Cho et al 2006)

Curcumin – is one of the most widely studied dietary chemopreventive agents for colon cancer prevention, however, its effects on epigenetic alterations, particularly DNA methylation, remain unclear. Using systematic genome-wide approaches, we aimed to elucidate the effect of curcumin on DNA methylation alterations in colorectal cancer cells. Our data provide previously unrecognized evidence for curcumin-mediated DNA methylation alterations as a potential mechanism of colon cancer chemoprevention. In contrast to non-specific global hypomethylation induced by 5-aza-CdR, curcumin-induced methylation changes occurred only in a subset of partially-methylated genes, which provides additional mechanistic insights into the potent chemopreventive effect of this dietary nutraceutical. (Link et al 2013)

Echinacea – The aims of this study were to provide a preliminary validation of the effects of 50% aqueous ethanol extract of Echinacea purpurea flowers and its major compound, cichoric acid, on human colon cancer cells Caco-2 and HCT-116. Our data indicate that cichoric acid has a strong growth-inhibitory effect against colon cancer cells, presumably resulting from the reduced telomerase activity and the induction of apoptosis. The exact mechanism of action should still be determined in future studies. Overall, the effects of 50% aqueous ethanol extract of E. purpurea flowers and cichoric acid may have provided in vitro evidence for the use as chemotherapeutic agents. (Tsai et al 2012)

EGCG – The present study shows that the polyphenols (−)-epigallocatechin-3-gallate (EGCG) and genistein (GEN) as well as two oxidative methyleugenol (ME) metabolites 3′-OXO-MIE and MEE potently diminished the activity of HDAC in intact colon carcinoma cells. (Groh et al 2013) 

Exercise – Six weeks of regular exercise suppressed the generation of aberrant crypt foci (ACF) in the colon by AOM. Expression of iNOS was decreased by exercise compared with that in sedentary mice along with lower nitrotyrosine level while COX-2 was not changed by either AOM or exercise. Additionally, tumor necrosis factor alpha (TNFalpha) was decreased by exercise in the colon and plasma. There was no effect of exercise on the expression of antioxidant enzymes and chaperon protein in the colon. Our results suggest that regular exercise prevents colon tumorigenesis, at least partly via the suppression of iNOS expression associated with anti-inflammation. (Aoi et al 2010)

Folate – It can be concluded that folate supplementation exerts a potent protective effect on rat colon carcinogenesis via significant modulation of DNA repair, providing a mechanism by which it plays a role in the etiology of human cancer. (Sadik & Shakere 2012)  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) 

Inositol hexaphosphate (IP6) – Proinflammatory cytokine IL-1β upregulates MMP and TIMP mRNAs expression in colon cancer epithelial cells Caco-2. Inositol hexaphosphate (IP6) (2.5 mM) influences constitutive expression of both MMP and TIMP genes and downregulates IL-1β stimulated transcription of some of these genes. IP6 exerts its anti-metastatic activity through modulation of MMP and TIMP genes expression to prevent cancer cell migration and invasion. (Kapral et al 2012)

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)

Modified citrus pectin (MCP) – Due to its anti-adhesive, apoptosis-promoting, and apoptosis-inducing properties, it appears that MCP is capable of targeting multiple critical rate-limiting steps involved in cancer metastasis. In addition, by inhibiting Galectin-3 anti-apoptotic function and enhancing apoptosis induced by cytotoxic drugs, it holds the potential to increase dramatically the efficiency of a conventional chemotherapy. (Glinksy & Raz 2009)

Olive oil — Inhibition of proliferation by extra-virgin olive oil crude phenolic extracts Arbequina variety extract was accompanied by apoptosis in both SW480 and HT29 colon-cancer-cell lines and a limited G₂M cell-cycle arrest in the case of SW480 human colon adenocarcinoma cells. (Fernandez-Arroyo et al 2012)

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)

Panax notoginseng – The anti-proliferation effects of four major single compounds from notoginseng flower extract (NGF), ginsenosides Rb1, Rb3, Rc and Rg3 were analyzed. Both 5-FU and NGF inhibited proliferation of HCT-116 human colorectal cancer cells.  This study demonstrates that NGF can enhance the anti-proliferation effect of 5-FU on HCT-116 human colorectal cancer cells and may decrease the dosage of 5-FU needed for colorectal cancer treatment. (Wang et al 2007)

Pterostilbene – In comparison, pterostilbene (PS) was a more potent chemopreventive agent than resveratrol (RS) for the prevention of colon cancer. This is also the first study to demonstrate that PS is a Nrf2 inducer and aldose reductase inhibitor in the azoxymethane-treated colon carcinogenesis model. (Chiou et al 2011) 

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) 

Rosmarinic acid – (in holy basil and rosemary) – This study aimed to investigate the effect of Rosmarinic acid (RA) on the development of intestinal adenomas in the Apc(Min) mouse model of colorectal carcinogenesis, and to correlate efficacy with levels of RA achieved in the plasma and gastrointestinal tract. Chronic consumption of RA furnished quantifiable levels of parent compound in the plasma and intestinal tract of Apc(Min) mice and may slow adenoma development. (Karmokar et al 2012)

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)

Sulforaphane – These results suggest that sulforaphane may be useful as a chemopreventive agent in colon cancer with inactivated or lost p53. (Rudolf & Cervinka 2011)

Ursolic acid – Overall, our results show that ursolic acid can inhibit the growth and metastasis of colorectal cancer and further enhance the therapeutic effects of capecitabine through the suppression of multiple biomarkers linked to inflammation, proliferation, invasion, angiogenesis, and metastasis. (Prasad et al 2012)

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)

References
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