Incidence and mortality rates (estimated, all sexes) for colorectal cancer, globally and within Asia and selected regions.
Abstract
Incidence rates vary 10-fold globally for colorectal cancer (CRC). Asia has lower rates than Western countries, but as the Western life-style becomes more prevalent in economically developing Asian countries, rates are increasing. Clinical therapy has improved over the last few decades, and national screening programmes are a proven and effective means of reducing mortality; chemoprevention through diet and life-style choices may provide additional value. Diet has strong associations with the aetiology of CRC, considerable epidemiological evidence exist that fruits and vegetables are associated with reduced risk of CRC. There is also extensive experimental evidence that phytochemicals from fruit and vegetables can modulate pathways of carcinogenesis. In this chapter, we consider Malaysia specifically, with its rich ethnopharmacological heritage and megabiodiversity; Malaysian natural compounds may be a source of potentially chemo-protective with relevance to CRC.
Keywords
- colon cancer
- in vitro
- Malaysia
- plants
- anticancer
1. Introduction
Botanically, Malaysia is one of the most bio-diverse countries in the world with more than 23,000 plant species recorded [1]. Many components of these plants are traditionally used for flavour and fragrances as well as for medicinal purposes. In line with bio-prospecting trend to find new pharmaceutical lead compounds for medical applications; researchers from local academic and research institutions within Malaysia have initiated investigations of the bioactive properties of various native plants. In Malaysia, colorectal cancer is the second most frequent cancer after breast cancer [2]. The aim of this review is to collate data and conclusions from recent studies undertaken on indigenous Malaysian plants with a view toward prevention and/or treatment of colorectal cancer (CRC).
2. Epidemiology of CRC
The geographical distribution of CRC differs significantly (~10-fold) across the world with the highest incidence rates in Australia/New Zealand (age-specific rate; ASR 44.8 and 32.2 per 100,000 in men and women, respectively), North America (ASR 30.1 and 22.7 per 100,000), Europe (ASR 37.3 and 22.7 per 100,000), and Japan (ASR 42.1 and 23.5 per 100,000). The lowest incidence rates occur in West Africa (ASR 4.5 and 3.8 per 100,000) although in this case, under-reporting is likely due to incomplete coverage by registries [2].
The global rise of incidence and mortality rates attributable to cancer is likely due to the ageing population, with incidence predicted to increase to 22.2 million cases globally by 2030 [3]. The cancer pattern among countries exhibits a strong societal and economic influence, where countries with a low human development index (HDI) (composite measure of life expectancy, education, and gross domestic product per head) tend to have higher levels of infection-related cancers (i.e., cervical) compared to medium and high HDI countries where the cancer burden is more commonly related to reproductive, dietary, and hormonal factors (e.g., lung, breast, and colorectal) [3]. As such, it is clear that CRC incidence rates increase in accordance with a country’s income [4].
Asia as a whole consists mainly of developing countries and as such, incidence rates of CRC (ASR 16.5 and 11.1 per 100,000 in men and women, respectively) are noticeably lower than for the mainly developed countries of Europe—both in terms of incidence and in mortality (Table 1). However, cancer incidence and mortality in Asia is likely to rise over the next 20 years, due in part to a rapid population expansion that will not be experienced by Western countries. This increase will clearly impact on the health care burden associated with cancer, and also quality of life across Asia as a whole. Ng and colleagues [4] recently considered the wide variation in cancer incidence and mortality across Asia with respect to cancer survival, defining it in terms of mortality to incidence ratios (MIR = 1 no effect on survival). Although cancer incidence is lower in Asia, cancer survival is higher in Western countries as the MIRs are lower. Moreover, while Eastern and Western Asia have a higher incidence of CRC compared to South-Eastern and South-Central Asia, the pattern for survival is reversed in that the latter two regions have poorer survival than Western and Eastern Asia [4]. In Malaysia (South Eastern Asia), CRC is the second most common malignancy after breast cancer, while incidence rates exceed that of China, cancer survival is similar. By contrast, in Japan, both incidence and survival are higher.
2.1. CRC pathogenesis
The majority of colorectal malignancies occur as sporadic forms that appear to arise from benign adenomatous polyps, with carcinomas emerging slowly over a period of 10–20 years [6–9]. Epidemiological data indicate that incidence and mortality rates of colorectal cancers (CRC) are greatly influenced by age rather than by gender. The majority of cases are detected in individuals over the age of 60 [10], with 55% of cases occurring in more developed regions in contrast to 52% of all CRC deaths which occur in the less-developed regions of the world, reflecting poorer survival. For individuals diagnosed with CRC, it has been determined that the 5-year survival rate is approximately 50–60% [11] and that survival among CRC patient is improved if WCRF/AICR lifestyle guidelines on physical activity, body fatness, and diet are adhered to [12]. The age-dependent increase in CRC development is associated with a multi-step oncogenesis process and a number of histological stages, reflecting the accumulation of genetic errors in somatic cells over time. Sporadic CRC is currently thought to arise via 1 of 3 identified molecular pathways (Micro Satellite instability—MSI, Chromosomal Instability—CIN and CpG island methylator phenotype—CIMP) depending upon the individual’s complement of gene alterations [13]. Conversely, the inheritance of germline mutations may also result in development of neoplasms at an early age, with approximately 5% of CRC cases being due to inherited single-gene syndromes such as familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) [14]. It is estimated that as much as 12–35% of colon cancers can be explained by heritable factors, but known single-nucleotide polymorphisms appear to explain only a small proportion of these [15].
The high degree of molecular heterogeneity present in CRC is reflected by the effectiveness of chemotherapeutic regimes; however, the clinical significance of the majority of these individual molecular alterations is still to be fully determined [16]. From a treatment perspective, early-stage CRC is managed by surgical resection and advanced CRC with a combination of chemotherapy and surgery. Most chemotherapeutic regimes use 5-Fluorouracil (5-FU) as the main cytotoxic agent and this is commonly administered in conjunction with oxaliplatin for adjuvant therapy for high-risk stage II/stage III CRC, and with either oxaliplatin or irinotecan for metastatic CRC. Furthermore, the addition of bevacizumab-based chemotherapy (a vascular endothelial growth factor (VEGF)-targeted agent) has proven to be more effective than cytotoxic chemotherapy alone for the treatment of metastatic CRC [17].
While there is no doubt that CRC treatments have advanced over the last decade, improvement in disease outcome has been more modest relative to the increase in treatment costs. Thus, population screening is an important and cost-effective strategy given the improved prognosis with early detection [18]. The pathogenesis of CRC makes it very well suited to population screening especially given the correlation between disease stage and mortality. It is clear that the detection and the removal of cancer precursors can reduce CRC incidence and mortality and effective detection of CRC allows for less invasive treatment with a better prognosis. As is to be expected, a large variation exists globally in the implementation of screening programmes both in terms of strategy used (organised vs opportunistic) and standards applied (diagnostic test, detection threshold), with implementation more common in Western countries [19]. Europe for the most part has implemented an organized screening programme, while the USA operates an opportunistic approach. In Asia, several countries have already developed organized programmes including Japan, Korea and, to a lesser extent, China. As yet, however, Malaysia has no organized screening in place. As cancer incidences are likely to continue to rise, screening programmes will necessarily become more of an issue for low resource countries. Moreover, as cancer pattern types change, there will arise a need to developed tailored approaches [19].
Region | Incidence | Mortality | 5-year prevalence | |||
---|---|---|---|---|---|---|
Number | ASR (W) | Number | ASR (W) | Number | Prop | |
Australian/New Zealand | 18887 | 38.2 | 5489 | 10 | 54266 | 245.4 |
Europe | 447136 | 29.5 | 214866 | 12.5 | 1203943 | 192.3 |
North America | 158169 | 26.1 | 63465 | 9.4 | 486650 | 172.9 |
Asia | 607182 | 13.7 | 331615 | 7.2 | 1493520 | 47 |
|
||||||
Eastern Asia (EA) | 421343 | 18.4 | 207716 | 8.4 | 1130066 | 87.1 |
Western Asia (WA) | 27140 | 14.8 | 15306 | 8.4 | 62162 | 37.5 |
South Eastern Asia (SEA) | 69016 | 12.5 | 43234 | 7.9 | 158845 | 35.7 |
South Central Asia (SCA) | 89683 | 6.1 | 65359 | 4.4 | 142447 | 11.3 |
|
||||||
Australia | 15869 | 38.4 | 4168 | 9 | 45622 | 245.8 |
Japan (EA) | 112675 | 32.2 | 49345 | 11.9 | 384877 | 350.8 |
UK | 40755 | 30.2 | 16202 | 10.7 | 104047 | 200.5 |
Malaysia (SEA) | 4539 | 18.3 | 2300 | 9.4 | 9714 | 47 |
China (EA) | 253427 | 14.2 | 139416 | 7.4 | 583054 | 52.7 |
Saudi Arabia (WA) | 2047 | 11.6 | 1094 | 6.6 | 4486 | 22.3 |
India (SCA) | 64332 | 6.1 | 48603 | 4.6 | 86650 | 9.8 |
2.2. Diet and CRC
The relatively recent increase in CRC incidence in Japan (Eastern Asia) and in urbanized regions of China (Eastern Asia) is of significant concern [20] and is thought to be due to the adoption of a more a Western lifestyle and diet [21]. Diet plays a central role in CRC pathogenesis, as those rich in saturated animal fat, and red meat (especially processed meat) [22] together with alcohol intake [23] and smoking [24] have been positively associated with colorectal neoplasia. Fruit and vegetable consumption is associated with a reduction in the risk of CRC [25], and this concept is supported by a large body of case-control studies, although results from cohort or prospective studies are less convincing [26]. Nevertheless, the protective effects of fruits and vegetables against colorectal cancer are attributed to the large number of bioactive phytochemicals present within them [27], comprising mainly plant polyphenolic secondary metabolites [28] and plant structural and storage polysaccharides which make up dietary fiber [29, 30]. These various plant components or natural products are found within a range of indigenous Malaysian fruit and vegetables, and thus may potentially play a role in chemoprevention for CRC.
3. Natural product research in Malaysia
Natural products include a large and diverse group of substances produced by a variety of sources including marine organisms, bacteria, yeasts, fungi, and plants [31]. Research on natural products has focused primarily on the chemical properties, biosynthesis, and biological functions of secondary metabolites [32]. Natural products, in particular plants, have been used in traditional medicine and health practice. The World Health Organization has acknowledged traditional medicine as a contributor to achieve health care objectives [33] and Malaysia, blessed with its megabiodiversity and rich ethnopharmacological heritage, has been observed to elegantly capitalize on these attributes with a view toward boosting the wealth and wellness of its population [34].
In late 2010, the Malaysian government launched the Economic Transformation Programme (ETP), which focuses on 12 National Key Economic Areas (NKEAs). The Agriculture sector, under the purview of the Ministry of Agriculture (MoA) is one of the NKEA-identified areas where the Entry Point Project 1 (EPP1) is focused on high-value herbal products. The MoA has overseen the establishment of five R&D clusters, which focus on, respectively, discovery, crop production, and agronomy, standardization and product development, toxicology/pre-clinical and clinical studies, and processing technology. The initial phase of this EPP was focused on ensuring the supply of five main local herbs, namely Tongkat Ali (
In Malaysia, research on natural products including the EPP-listed local herbs described above is being undertaken by research centers and institutions of higher learning (Table 2). Nevertheless, research in this area is also being carried out by various independent research groups in the local academia.
Entities | Institutions |
---|---|
Advanced Medical and Dental Institute | Universiti Sains Malaysia (USM) |
Atta-ur-Rahman Institute for Natural Product Discovery | Universiti Teknologi MARA (UiTM) |
Bioresource and Drug Discovery Research Group (BDD), Faculty Science and Natural Resources (FSSA) | Universiti Malaysia Sabah (UMS) |
Centre For Natural Products And Drug Research (CENAR) | Universiti Malaya (UM) |
Drug Discovery and Development Research Group (under purview of the Natural Products Cluster) | Universiti Kebangsaan Malaysia (UKM) |
Institute of Bioproduct Development (IBD) | Universiti Teknologi Malaysia |
Laboratory of Natural products, Institute of Bioscience | Universiti Putra Malaysia (UPM) |
Natural Medicine Products Centre (NMPC) | International Islamic University Malaysia (IIUM) |
Natural Product and Drug Discovery Centre (NPDC) | Malaysian Institute of Pharmaceuticals and Nutraceuticals (IPharm) |
Natural Product Lab, Institute of Marine Biotechnology | Universiti Malaysia Terengganu (UMT) |
Natural Products Division | Forest Research Institute Malaysia (FRIM) |
4. Studies of the effect of Malaysian plants on colon cancer
It has been estimated that around 1200 medicinal plants have potential pharmaceutical value [1]. Many of these species have been scientifically investigated by researchers seeking to provide evidence of effectiveness toward different diseases such as cancer, diabetes, arthritis, heart diseases, and many others. However, work on the effects of Malaysian plants on colon cancer specifically has been very limited (Tables 3 and 4). Nonetheless, several observations may be made on work undertaken to date that allow trends to be identified for the future of such work.
It is clear that there is no focused approach on any particular species, and most of the studies were conducted at the early stage of screening for anti-cancer effects with little in the way of continued development thereafter. This work includes cytotoxicity screening of crude extracts or compounds derived from solvent fractions against several types of cancer using
Plant and part of plant used | Common name | Compound/extract tested |
Type of study | Details/IC50 | Reference |
---|---|---|---|---|---|
Graviola, soursop; adurian belanda | Ethyl acetate extract | and CCD841 cell lines |
IC50 = 4.29 ± 0.24 μg/ml (HT29) IC50 = 3.91 ± 0.35 μg/ml (HCT116) IC50 = 34.24 ± 2.12 μg/ml (CCD841) |
[36] | |
5-Fluorouracil (positive control) IC50 = 1.10 ± 0.11 μg/ml (HT29) IC50 = 0.90 ± 0.09 μg/ml (HCT116) |
|||||
The extract also showed cell cycle arrest at G1, induction of apoptosis, anti-migration and anti-invasive effects. |
|||||
|
Graviola, soursop; adurian belanda | Ethyl acetate extract | and CCD 841 cell lines. |
HT29 IC50 = 5.72 ± 0.41 μg/ml (12 h) IC50 = 3.49 ± 0.22 μg/ml (24 h) IC50 = 1.62 ± 0.24 μg/ml (48 h) |
[37] |
CCD 841 IC50 = 64.32 ± 3.76 μg/ml (12 h) IC50 = 47.10 ± 0.47 μg/ml (24 h) IC50 =32.51 ± 1.18 μg/ml (48 h) |
|||||
cancer in rats |
Aberrant Crypt formation after 2 weekly injections of extract. 250 mg/kg = 61.2% inhibition 500 mg/kg = 72.5% inhibition 5-FU = 79.5% inhibition |
||||
|
Mangosteen; amanggis | Xanthone (81% α-mangostin and 16% γ- mangostin) from toluene extract of the fruit α-mangostin γ-mangostin) |
HCT 116 cell line Subcutaneous tumor of HCT116 on nude mice |
1) IC50 = 6.5 ± 1.0 μg/ml 2) IC50 = 5.1 ± 0.2 μg/ml 3) IC50 = 7.2 ± 0.4 μg/ml IC50 of Cisplatin (positive control) = 6.1 ± 0.2 μg/ml The extract also showed induction of apoptosis, anti- tumorigenicity and up- regulation of MAPK/ERK, c-Myc/Max, and p53 cell signalling pathways growth inhibition of the subcutaneous tumor |
[38] |
|
Mangosteen; amanggis | Hexane and ethyl acetate (Other extracts produced, butanol and methanol) | Caco-2 cell line (also tested on other cells KB and PBMC) |
IC50 = 13.0 ± 3.8 μg/ml (Hexane) IC50 = 8.1 ± 0.1 μg/ml (Ethyl acetate) IC50 of Tamoxifen positive control = 4.0 ± 0.4 μg/ml |
[39] |
|
Mangosteen; amanggis | α-mangostin β-mangostin γ-mangostin hexane extracts |
DLD-1 cells |
All three extracts showed anti-proliferative effects at 20 μM. |
[40] |
Plant and part of plant used |
Common name | Compound/extract tested |
Type of study | Details/IC50 | References |
---|---|---|---|---|---|
|
aTepus | Methanol and fractionated extracts (hexane, ethyl acetate and water) |
HT 29 and HCT 116 cell line (also tested on other cell lines; KB, CasKi, MCF-7, A549 and MRC-5) |
Hexane extracts showed IC50 of 36.1 ± 1.1 μg/ml (HCT116) and 47.4 ± 1.6 μg/ml (HT29) Ethyl acetate extracts showed IC50 of 20.4 ± 3.2 μg/ml (HCT116) and 24.2 ± 0.04 μg/ml (HT29) Methanol and water extracts showed IC50 of more than 100 μg/ml IC50 of doxorubicin (positive control) = 0.24 ± 0.04 μg/ml (HCT116) and 0.33 ± 0.03 μg/ml (HT29) |
[41] |
|
aSimmilit matangi aRambai aNaga buana aPecah kaca/Pecah beling/Pokok pecah/Jin batu/ |
Hexane, dichloromethane, ethyl acetate and methanol extracts, respectively |
HT29 cell line (also tested on other cell lines; MCF-7, DU- 145 and H460) |
DCM extract of root showed the lowest IC50 among the extracts tested against HT29 cells (IC50 = 8.1 ± 0.5 μg/ml) |
[42] |
|
aTemu pauh/Kunyit mangga | Crude methanol and fractionated extracts (hexane, ethyl acetate) |
HT 29 and HCT 116 cell line(also tested on other cell lines; KB, CasKi, MCF-7, A549 and MRC-5) |
Extracts showed the IC50 between 29.4 ± 0.2 and 36.8 ± 3.8 μg/ml against HCT116 cells Extracts showed the IC50 between 17.9 ± 0.3 and 22.0 ± 1.1 μg/ml against HT29 cells IC50 of doxorubicin (positive control) = 0.24 ± 0.04 μg/ml (HCT116) and 0.33 ± 0.03 μg/ml (HT29) Isolated compounds from the extracts also showed high cytotoxicity effects towards both cell lines (between 6.3 ± 0.26 and 14.9 ± 0.40 μg/ml) Several isolated compounds from the extracts also showed considerable cytotoxicity effects against the cancer cells |
[43] |
|
aTemu pauh/Kunyit mangga | Hexane and ethyl acetate extracts. |
HT29 and CCD-18Co |
Hexane: IC50 = 17.9 ± 1.2 μg/ml (HT29) IC50 = 45.7 ± 1.0 μg/ml (CCD-18Co) Ethyl acetate: IC50 = 15.6 ± 0.8 μg/ml (HT29) IC50 = 46.5 ± 0.1 μg/ml (CCD-18Co) |
[44] |
|
aJarum tujuh bilah | Compounds from ethyl acetate fraction
|
HCT 116 cell line (also tested on other cell lines; KB, CasKi, MCF-7, A549 and MRC-5) |
Dihydroactinidiolide showed the lowest IC50 at 5 μg/ml against HCT116 cells Dihydroactinidiolide showed IC50 of 91.3 μg/ml against MRC-5 cells IC50 of doxorubicin (positive control) = 0.36 μg/ml (HCT116) and 0.55 μg/ml (MRC-5) |
[45] |
|
aSirih | Aqueous extract | HCT 116 and HT29 cell lines |
In the presence of the extract, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, the extract did not significantly reduce 5-FU dosage in HCT116 cells |
[46] |
|
aPecah kaca/Pecah beling/Pokok pecah/Jin batu/ | Crude ethanol extract and fractions obtained from column chromatography |
In vivo Sprague Dawley (SD) male rats HT29, CCD841 |
protects against CRC formation (azoxymethane- induced aberrant crypt foci) in rats Exposure of HT29 and CCD-841 to extract and several fractions (tested between 0 and 500 μg/ml) induced a concentration dependent decrease in cell viability |
[47] |
|
Ginger; ahalia | Ginger: Water- based ultrasonic assisted extraction Honey: Packaged in plastic containers and sterilized using gamma radiation |
HT29 cell lines |
IC50 = 5.2 mg/ml (ginger alone) IC50 = 80 mg/ml (Gelam honey alone) The combinations of 3 and 4 mg/ml of ginger with 27 and 10 mg/ml of Gelam honey showed combination index (CI) values of 0.92 and 0.90, respectively, indicating synergistic effects. Cell death in response to the combined ginger and Gelam honey treatment was associated with the stimulation of early apoptosis |
[48] |
|
Ginger; ahalia | Ethanol extract | HCT 116 and HT29 cell lines |
Inhibition of proliferation IC50 (HCT116) = 496 ± 34.2 μg/ml IC50 (HT29) = 455 ± 18.6 μg/ml Induction of apoptosis at 500 μg/ml extract 35.05% (HCT116) and 19.81% (HT29) Ginger extract arrested HCT 116 and HT 29 cells at G0/G1 and G2/M phases with corresponding decreased in S-phase |
[49] |
Some species investigated for their effects against colon cancer in the listed studies have also been investigated for other biological effects. For example, prior to the report by Abdul Malek et al. [43],
For
The colon cancer cell lines used in the studies differ in their origin, mutation status and metabolic requirements [52]. For example, HT29 cells utilize glucose through the pentose phosphate pathway [53], whereas HCT116 cells have higher requirements for glutamine [52, 54]. In terms of gene expression, HT29 is deficient in expression of p53 [55], while HCT116 cells possess mutations in PI3KCA and KRAS genes which confer constitutive activation of PI3K/AKT and KRAS pathways [56]. Since the two cells lines have different characteristics, the use of such cell lines in preliminary studies is substantial as it can set forth the mechanistic investigations on the effects of the plants against colon cancer.
Although the majority of work was
Compounding the lack of consensus and technical variability is the fact that choice of journals in which to publish is still very much dependent on funding; thus, publishing in the open access journals with high impact factors can only be afforded by certain groups of researchers. This clearly will have hampered the dissemination of research data as, while it may be beneficial for researchers to reach a wider audience at the early stage of work, this may correspond to having to publish in a low-cost, lower impact journals due to lack of funding. From another perspective, higher impact journals often require more conclusive data, which in turn means more experimental work—early stage work may not meet such journals’ publication criteria and may be perceived to be low quality. Therefore, it would be more favorable to have a mechanism to help improve the dissemination of work in order to enhance the overall research and development in the subject area.
Based on the publications considered in Tables 3 and 4, it was also observed that authors did not always report the local names of species investigated. Since these are local plants that may not even have English names, it is to be recommended that this information is included together with full description of the species investigated. This could be one way to present the potential positive effects of the species to a wider scientific community thereby increasing the impact and scientific value of the work. Thus, the correct taxonomy including genus, species and family should be given for accuracy.
5. Conclusion
Some Malaysian plants that show anti-cancer effects towards colon cancer include
Nevertheless, much of the scientific evidence is preliminary at best despite the selection of plant species for study based upon ethnomedicinal practices. The introduction of the EPP by the Malaysian government is a commendable effort to raise the value of indigenous Malaysian plants in the pharmaceutical sector. However, a more concerted approach to the work is necessary including a comprehensive review of the existing data in order to fully exploit local plants toward prevention and treatment of colon cancer.
Acknowledgments
We wish to thank Dr. Rashidi Othman, Kulliyyah of Architecture and Environmental Design (KAED), International Islamic University Malaysia (IIUM) for his valuable comments.
References
- 1.
Aman R. Tumbuhan Liar Berkhasiat Ubatan (Wild Plants with Medicinal Properties). Kuala Lumpur: Dewan Bahasa dan Pustaka; 2006. 12-14. ISBN: 9789836281517 - 2.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136. doi:10.1002/ijc.29210 - 3.
Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the Human Development Index (2008–2030): a population-based study. Lancet Oncol. 2012;13(8):790–801. doi:10.1016/S1470-2045(12)70211-5 - 4.
Ng CJ, Teo CH, Abdullah N, Tan WP, Tan HM. Relationships between cancer pattern, country income and geographical region in Asia. BMC Cancer. 2015;15:613. doi:10.1186/s12885-015-1615-0 - 5.
WHO (World Health Organization). GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. [internet]. 2012. Available from: http://globocan.iarc.fr.[Accessed:2016-01-20] - 6.
Peipins LA, Sandler RS. Epidemiology of colorectal adenomas. Epidemiol Rev. 1994;16(2):273–97. - 7.
Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87(2):159–70. doi:10.1016/S0092-8674(00)81333-1 - 8.
Brenner H, Hoffmeister M, Stegmaier C, Brenner G, Altenhofen L, Haug U. Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840 149 screening colonoscopies. Gut. 2007;56(11):1585–9. doi:10.1136/gut.2007.122739 - 9.
Kuntz KM, Lansdorp-Vogelaar I, Rutter CM, Knudsen AB, van Ballegooijen M, Savarino JE, et al. A systematic comparison of microsimulation models of colorectal cancer: the role of assumptions about adenoma progression. Med Decis Mak. 2011;31(4):530–9. doi:10.1177/0272989X11408730 - 10.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107 - 11.
WCRF. Food, nutrition and the prevention of cancer: a global perspective [comprehensive report]. World Cancer Research Fund/American Institute for Cancer Research, Washington, DC; 2006. - 12.
Romaguera D, Ward H, Wark PA, Vergnaud AC, Peeters PH, van Gils CH, Ferrari P, Fedirko V, Jenab M, Boutron-Ruault MC, Dossus L, Dartois L, et al. Pre-diagnostic concordance with the WCRF/AICR guidelines and survival in European colorectal cancer patients: a cohort study. BMC Med. 2015;13:107. doi:10.1186/s12916-015-0332-5 - 13.
Carethers JM, Jung BH. Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology. 2015;149(5):1177–1190. doi:10.1053/j.gastro.2015.06.047 - 14.
Lang M, Gasche C. Chemoprevention of colorectal cancer. Dig Dis. 2015;33(1):58–67. doi:10.1159/000366037 - 15.
Jiao S, Peters U, Berndt S, Brenner H, Butterbach K, Caan BJ, et al. Estimating the heritability of colorectal cancer. Hum Mol Genet. 2014;23(14):3898–905. doi:10.1093/hmg/ddu087 - 16.
Shiovitz S, Grady WM. Molecular markers predictive of chemotherapy response in colorectal cancer. Curr Gastroenterol Rep. 2015;17(2):431. doi:10.1007/s11894-015-0431-7 - 17.
Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9. doi:10.1200/JCO.2007.14.9930 - 18.
Lansdorp-Vogelaar I, Knudsen AB, Brenner H. Cost-effectiveness of colorectal cancer screening. Epidemiol Rev. 2011;33:88–100. doi:10.1093/epirev/mxr004 - 19.
Schreuders EH, Ruco A, Rabeneck L, Schoen RE, Sung JJ, Young GP, Kuipers EJ. Colorectal cancer screening: a global overview of existing programmes. Gut. 2015;64(10):1637–49. doi:10.1136/gutjnl-2014-309086 - 20.
Sung JJ, Ng SC, Chan FK, et al. An updated Asia Pacific Consensus Recommendations on colorectal cancer screening. Gut. 2015;64:121–32. doi:10.1136/gutjnl-2013-306503 - 21.
Sung JJ, Lau JY, Goh KL, Leung WK. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol. 2005;6:871–6. doi:10.1016/S1470-2045(05)70422-8 - 22.
Carr PR, Walter V, Brenner H, Hoffmeister M. Meat subtypes and their association with colorectal cancer: systematic review and meta-analysis. Int J Cancer. 2016;138(2):293–302. doi:10.1002/ijc.29423 - 23.
Fedirko V, Tramacere I, Bagnardi V, Rota M, Scotti L, Islami F, Negri E, Straif K, Romieu I, La Vecchia C. Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Ann Oncol. 2011;22:1958–1972. doi:10.1093/annonc/mdq653 - 24.
Gong J, Hutter C, Baron JA, Berndt S, Caan B, Campbell PT, Casey G, Chan AT, Cotterchio M, Fuchs CS. A pooled analysis of smoking and colorectal cancer: timing of exposure and interactions with environmental factors. Cancer Epidemiol Biomark Prev. 2012;21:1974–1985. doi:10.1158/1055-9965.EPI-12-0692 - 25.
Bradbury KE, Appleby PN, Key TJ. Fruit, vegetable, and fiber intake in relation to cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). Am J Clin Nutr. 2014;100(Supplement 1):394S–8S. doi:10.3945/ajcn.113.071357 - 26.
Leenders M, Siersema PD, Overvad K, Tjønneland A, Olsen A, Boutron-Ruault M-C, et al. Subtypes of fruit and vegetables, variety in consumption and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2015;137(11):2705–14. doi:10.1002/ijc.29640 - 27.
Li YH, Niu YB, Sun Y, Zhang F, Liu CX, Fan L, Mei QB. Role of phytochemicals in colorectal cancer prevention. World J Gastroenterol. 2015;21(31):9262–72. doi:10.3748/wjg.v21.i31.9262 - 28.
Núñez-Sánchez MA, González-Sarrías A, Romo-Vaquero M, García-Villalba R, Selma MV, Tomás-Barberán FA, García-Conesa MT, Espín JC. Dietary phenolics against colorectal cancer—from promising preclinical results to poor translation into clinical trials: pitfalls and future needs. Mol Nutr Food Res. 2015;59(7):1274–91. doi:10.1002/mnfr.201400866 - 29.
Fung KY, Cosgrove L, Lockett T, Head R, Topping DL. A review of the potential mechanisms for the lowering of colorectal oncogenesis by butyrate. Br J Nutr. 2012;108(5):820–31. doi:10.1017/S0007114512001948 - 30.
van Dijk M, Pot GK. The effects of nutritional interventions on recurrence in survivors of colorectal adenomas and cancer: a systematic review of randomised controlled trials. Eur J Clin Nutr. 2016. doi:10.1038/ejcn.2015.210. [Epub ahead of print] - 31.
NCCIH (National Centre for Complementary and Integrative Health). [Internet]. 2015. Available from: https://nccih.nih.gov/grants/naturalproducts [Accessed: 2015-12-04] - 32.
Editorial. All natural. Nat Chem Biol. 2007;3:351. doi:10.1038/nchembio0707-351 - 33.
WHO (World Health Organization). 1991. Report on the intercountry expert meeting of traditional medicine and primary health care. WHO-EMTRM/1-E/L/12.92/168, November 30–December 3, 1991, Cairo, Egypt. - 34.
Akarasereenont P, Datiles MJR, Lumlerdkij N, Yaakob H, Prieto JM and Heinrich M. A South-East Asian Perspective on Ethnopharmacology. In: Heinrich M, Jager A, editors. Ethnopharmacology. Wiley-Blackwell; 2015. pp. 317–328. doi:10.1002/9781118930717.ch27 - 35.
Performance Management & Delivery Unit; PEMANDU. [Internet]. 2013. Available from http://etp.pemandu.gov.my/Agriculture-@-Agriculture_-_EPP_1-;_High-Value_Herbal_Products.aspx#sthash.YK0kpNR8.dpuf. [Accessed: 2015-12-04] - 36.
Moghadamtousi SZ, Karimian H, Rouhollahi E, Paydar, Fadaeinasab M, Abdul Kadir H. Annona muricata leaves induce G1 cell cycle arrest and apoptosis through mitochondria-mediated pathway in human HCT-116 and HT-29 colon cancer cells. J Ethnopharmacol. 2014;156:277–289. doi:10.1016/j.jep.2014.08.011 - 37.
Moghadamtousi SZ, Rouhollahi E, Karimian H, Fadaeinasab M, Firoozinia M, Abdulla MA, Kadir HA. The chemopotential effect of Annona muricata leaves against azoxymethane-induced colonic aberrant crypt foci in rats and the apoptotic effect of acetogenin annomuricin E in HT-29 cells: a bioassay-guided approach. Plos One. 2015;10(4):e0122288. doi:10.1371/journal.pone.0122288 - 38.
Aisha AFA, Abu-Salah KM, Ismail Z, Majid AMSA. In vitro andin vivo anti-colon cancer effects ofGarcinia mangostana xanthones extract. BMC Complement Altern Med. 2012;12(1):1–10. doi:10.1186/1472-6882-12-104 - 39.
Khonkarn R, Okonogi S, Ampasavate C, Anuchapreeda S. Investigation of fruit peel extracts as sources for compounds with antioxidant and antiproliferative activities against human cell lines. Food Chem Toxicol. 2010;48(8–9):2122–2129. doi:10.1016/j.fct.2010.05.014 - 40.
Matsumoto K, Akao Y, Ohguchi K, Ito T, Tanaka T, Iinuma M, Nozawa Y. Xanthones induce cell-cycle arrest and apoptosis in human colon cancer DLD-1 cells. Bioorganic Med Chem. 2005;13(21):6064–9. doi:10.1016/j.bmc.2005.06.065 - 41.
Abdul Malek SN, Phang CW, Ibrahim H, Abdul Wahab N, Sim KS. Phytochemical and cytotoxic investigations of Alpinia mutica rhizomes. Molecules. 2011;16:583–589. doi:10.3390/molecules16010583 - 42.
Ismail M, Bagalkotkar G, Iqbal S, Adamu HA. Anticancer properties and phenolic contents of sequentially prepared extracts from different parts of selected medicinal plant indigenous to Malaysia. Molecules. 2012;17:5745–5756. doi:10.3390/molecules17055745 - 43.
Abdul Malek SN, Lee GS, Hong SL, Yaacob H, Abdul Wahab N, Weber J-FF, Ali Shah SA. Phytochemical and cytotoxic investigations of Curcuma mangga rhizomes. Molecules. 2011;16:4539–4548. doi:10.3390/molecules16064539 - 44.
Hong GW, Hong SL, Lee GS, Yaacob H, Malek SNA. Non-aqueous extracts of Curcuma mangga rhizomes induced cell death in human colorectal adenocarcinoma cell line (HT29) via induction of apoptosis and cell cycle arrest at G0/G1 phase. Asian Pac J Trop Med. 2016;9(1):8–18. doi:10.1016/j.apjtm.2015.12.003 - 45.
Abdul Malek SN, Sim KS, Abdul Wahab N, Yaacob H. Cytotoxic components of Pereskia bleo (Kunth) DC. (Cactaceae) leaves. Molecules. 2009;14:1713–1724. doi:10.3390/molecules14051713 - 46.
Ng PL, Rajab NF, Then SM, Mohd Yusof YA, Wan Ngah WZ, Pin KY, Looi ML. Piper betle leaf extract enhances the cytotoxicity effect of5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells. J Zhejiang Univ Sci B Biomed Biotechnol. 2014;15:692–700. doi:10.1631/jzus.B1300303 - 47.
Al-Henhena N, Khalifa SAM, Poh YYR, Ismail S, Hamadi R, Shawter AN, Mohd Idris A, Azizan A, Al-Wajeeh NS, Abdulla MA, El-Seedi. Evaluation of chemopreventive potential of Strobilanthes crispus against colon cancer formationin vitro andin vivo . BMC Complement Altern Med. 2015;15:419. doi:10.1186/s12906-015-0926-7 - 48.
Tahir AA, Sani NFA, Murad NA, Makpol S, Ngah WZW, Yusof YAM. Combined ginger extract & Gelam honey modulate Ras/ERK and PI3K/AKT pathway genes in colon cancer HT29 cells. Nutr J. 2015;14(1):1–10. doi:10.1186/s12937-015-0015-2 - 49.
Abdullah S, Zainal Abidin SA, Murad NA, Makpol S, Wan Ngah WZ, Mohd Yusof YA. Ginger extract ( Zingiber officinale ) triggers apoptosis and G0/G1 cells arrest in HCT 116 and HT 29 colon cancer cell lines. Afr J Biochem Res. 2010;4:134–142. ISSN: 1996-0778 - 50.
Mohamad H, Abas F, Permana D, Lajis NH, Alib AM, Sukaric MA, Hinc TYY, Kikuzakid H, Nakatanid N. DPPH free radical scavenger components from the fruits of Alpinia rafflesiana Wall. ex. Bak. (Zingiberaceae). Z. Naturforsch. 2004;59c:811–815. - 51.
Jantan I, Pisar M, Sirat HM, Basar N, Jamil S, Ali RM, Jalil J. Inhibitory effects of compounds from Zingiberaceae species on platelet activating factor receptor binding. Phytother Res. 2004;18:1005–1007. - 52.
Richard SM, Marignac MVL. Sensitization to oxaliplatin in HCT116 and HT29 cell lines by metformin and ribavirin and differences in response to mitochondrial glutaminase inhibition. J Cancer Res Ther. 2015;11:336–340. doi:10.4103/0973-1482.157317 - 53.
Vizán P, Alcarraz-Vizán G, Díaz-Moralli S, Solovjeva ON, Frederiks WM, Cascante M. Modulation of pentose phosphate pathway during cell cycle progression in human colon adenocarcinoma cell line HT29. Int J Cancer. 2009;124(12):2789–2796. doi:10.1002/ijc.24262 - 54.
Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA. 2010;107:8788–8793. doi:10.1073/pnas.1003428107 - 55.
Davidson D, Coulombe Y, Martinez Marignac V, Amrein L, Grenier J, Hodkinson K, et al. Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells. Investig New Drugs. 2012;30:1248–56. doi:10.1007/s10637-010-9626-9 - 56.
Wang J, Kuropatwinski K, Hauser J, Ross MR, Zhou Y, Conway A, et al. Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis. Mol Cancer Ther. 2007;6:1143–50. doi:10.1158/1535-7163.MCT-06-0555