This document summarizes and reviews several research studies on phytochemicals and their relationship to cancer risk and prevention. It discusses cancer statistics such as the most common cancer sites in the US. It also explores topics like nutrigenetics, chemoprevention, and how certain phytochemicals may play a role in reducing cancer risk. Two specific studies are summarized: one reviewing the effectiveness of apple and berry juices in preventing colon cancer, and another investigating the anti-cancer effects of morin, a flavonoid found in mulberry figs, on human leukemia cells.

1. Meredith College FN 601
Research Summaries
Winnie Lin, MS, DTR
Phytochemical, Cancer Risk and
Prevention

2. Background

3. Cancer Statistics
Top 10 Cancer Sites. http://apps.nccd.cdc.gov/uscs/toptencancers.aspx. Accessed February 8, 2015.

4. All Races
Characteristic Overall Men Women
All Cancers 64.9% 64.9% 65%
Age group at diagnosis
0-44 years 80.5% 75.7% 83.5%
45-54 years 71.4% 65.5% 76.3%
55-64 years 68.2% 67.9% 68.6%
65-74 years 64.0% 66.8% 60.1%
75+ years 51.8% 55.0% 48.8%
Specific primary site
Lung and bronchus 18.1% 15.4% 21.2%
Colon and rectum 63.4% 62.8% 63.9%
Female breast NA NA 88.1%
Cervix uteri NA NA 67.5%
Prostate NA 97.4% NA
Cancer Survivorship and Risk Factors
 Risk Factors (ACS): tobacco use, infection, diet and
body composition, and radiation
 Preventions: lifestyle and diet modifications, i.e. red meat
and colon cancer, salts and preservatives and gastric
cancer
 33% of common cancers in high-income countries are
preventable through adapting a healthy lifestyle
United States Cancer Statistics: 1999–2011 Incidence and Mortality Web-based Report. www.cdc.gov/uscs. Accessed February 8, 2015.
American Cancer Society http://canceratlas.cancer.org/risk-factors/cancer-risk-factors/. Accessed February 8, 2015

5. Nutrigenetics
 “[I]dentify the genetic markup of a particular
individual co-ordinates his or her response to various
dietary nutrients.”
 5,10-methylenetetrahydrofolate reductase (MTHFR)
gene is likely to require a more bioavailable form of
folate for optimal health.
 Twin studies have shown that the risk of identical
twins to develop the same cancer is <10%, of which
cancer risk is increased only if there is gene-diet
interaction .
Gaboon, NEA. Nutritional genomics and personalized diet. The Egyptian Journal of Medical Human
Genetics 2011; 12: 1-7.
Krause Food and The Nutrition Care Processes

6. Chemoprevention
 The intake of foreign agents in order to restrain induction,
to prevent or slow the progression of cancer, or reversal
of carcinogenesis at a premalignant stage.
 A use of pharmaceutical or nutraceutical agents, i.e.
phytochemicals via inactivation of reactive oxygen
species (ROS), or interruption of cell signaling pathways.
 González-Vallinas et al. have suggested that “the
strategies to research phytochemicals should mimic
those in the development of new targeted antitumor
drugs.”
 Primary (avoidance), secondary (detection and
elimination), and tertiary (preventing recurrence,
progression, and disease-related complications)
Gaboon, NEA. Nutritional genomics and personalized diet. The Egyptian Journal of Medical Human Genetics 2011; 12: 1-7.
Krause Food and The Nutrition Care Processes
Jaganathan SK, Vellayappan MV, Narasimhan G,et al. Chemopreventive effect of apple and berry fruits against colon cancer. World J
Gastroenterol. 2014; 20(45): 17029-17036 DOI: http://dx.doi.org/10.3748/wjg.v20.i45.17029
González-Vallinas M, González-Castejón M, Rodríguez-Casado A, Ramírez de Molina A. Dietary phytochemicals in cancer prevention and
therapy: a complementary approach with promising perspectives. Nutrition Reviews. 2013; 71 (9): 585-599. DOI: 10.1111/nure.12051.
Alberts DS, Hess LM. Fundamentals of Cancer Prevention. New York, Springer Verlag; 2008.

7. Phytochemical
Dietary phytochemicals in cancer prevention and therapy: a complementary approach with promising
perspectives. Margarita González-Vallinas et al.

8. Dietary phytochemicals in cancer prevention and therapy: a complementary approach with promising
perspectives. Margarita González-Vallinas et al.
Phytochemical

9. Phytochemical
Dietary phytochemicals in cancer prevention and therapy: a complementary approach with promising
perspectives. Margarita González-Vallinas et al.

10. Jaganathan SK et al.
Chemopreventive effect of apple and
berry fruits against colon cancer

11.  12 studies were reviewed on the effectiveness of
apple and berry juices in colon cancer prevention
 7 studies of polyphenols from apple juice
 hydroxycinnamic acids
 flavan-3-ols/procyanidins
 flavonols, dihydrochalcones, and
 anthocyanins
 5 studies of anthocyanin-rich extracts (AREs), β-
carotene, tangeretin from berry juice.
Jaganathan SK, Vellayappan MV, Narasimhan G,et al. Chemopreventive effect of apple and berry fruits against
colon cancer. World J Gastroenterol. 2014; 20(45): 17029-17036 DOI: http://dx.doi.org/10.3748/wjg.v20.i45.17029

12.  4 in vitro studies using colon cancer cell lines to study the
effect of apple juice on cancer cells, PKC activity in HT29
cells, oxidative damage, presence of butyl hydroperoxide-
induced ROS, cytochrome P450 1A1 enzyme and other
enzymes relevant to cancer etiology
 Artificial mixture imitating the natural polyphenolic property is less
effective than its natural counterpart, so as the isolated components
than the mixtures.
 In addition, SCFA has increased 1.5 fold in fermentation caused by
human fecal flora than non-fermented samples; it is known to stimulate
apoptosis.
 3 in vivo studies using rat models studied the numbers of
large aberrant crypt foci and stimulation of redox-sensitive
gene expression.
 Apple juices have no cancer preventative bioactivity in obese rats, while
pre-neoplastic lesions in the rats were reduced at different rates
according to the quantity of apple juices fed.
Jaganathan SK, Vellayappan MV, Narasimhan G,et al. Chemopreventive effect of apple and berry fruits against colon cancer. World J
Gastroenterol. 2014; 20(45): 17029-17036 DOI: http://dx.doi.org/10.3748/wjg.v20.i45.17029

13.  3 in vitro studies using human intestinal carcinoma cells
and the effect of AREs and flavonoids on their growth .
 Those cell growths are inhibited while NCM 460, normal epithelial
cells are found to grow unaffectedly.
 2 in vivo studies demonstrated purple corn extract and
lyophilized black raspberries
 Decrease in the prevalence of aberrant crypt foci and early
colon cancer lesions
 Inhibit colorectal cancer and/or polyp tissue.
 And, low dose of mirtocyan is associated with reduced circulating
insulin-like growth factor-1, which is procarcinogenic.
Jaganathan SK, Vellayappan MV, Narasimhan G,et al. Chemopreventive effect of apple and berry fruits against
colon cancer. World J Gastroenterol. 2014; 20(45): 17029-17036 DOI: http://dx.doi.org/10.3748/wjg.v20.i45.17029

14.  Cloudy liquid is found to be more effective than clear and
smoothie apple juices
 2 apples per day for humans may provide 4-10 mg
procyanidin to attain similar effect
 22 grams of chokeberry extract to obtain 1.3 grams of
cyanidin-3-glycoside (chrysanthemin), an anthocyanin
derivative.
 Limitations of the studies are those results are yielded in
vitro or in rat models which may not be as effective as in
human subjects
 The quantity of each phytochemicals required is not
demonstrated in every study reviewed.
 More large scale human trials are required to establish the
validity and practicality of fruit juice’s chemopreventive effects
in human colon cancer.
Jaganathan SK, Vellayappan MV, Narasimhan G,et al. Chemopreventive effect of apple and berry fruits against
colon cancer. World J Gastroenterol. 2014; 20(45): 17029-17036 DOI: http://dx.doi.org/10.3748/wjg.v20.i45.17029

15. Park et al.
Morin, a flavonoid from moraceae, induces
apoptosis by induction of BAD protein in
human leukemic cells

16.  Investigated the anti-cancer activity of morin in human
leukemic cells
 A flavonoid originally isolated from Moraceae family
 mulberry figs and Chinese herbs
 Regulates the inflammatory response, and suspenses
carcinogenesis and cancer progression.
 Apoptosis is the major mechanism that is suggested to be
responsible for the anti-cancer effects of fruits and
vegetables.
Park C, Lee WS, Go S, Nagappan A et al. Morin, a Flavonoid from Moraceae, Induces Apoptosis by Induction of
BAD Protein in Human Leukemic Cells. Int. J. Mol. Sci. 2015, 16, 645-659; doi:10.3390/ijms16010645.

17. Park C, Lee WS, Go S, Nagappan A et al. Morin, a Flavonoid from Moraceae, Induces Apoptosis by Induction of BAD Protein in
Human Leukemic Cells. Int. J. Mol. Sci. 2015, 16, 645-659; doi:10.3390/ijms16010645.

18.  HL-60, K562, THP-1, and U937 human leukemia cells
from the American type culture collection (Manassas, VA,
USA)
 Morin obtained from Aging Tissue Bank (Pusan, Korea)
 Cells were treated in the cell viability essay, MTT, for 48
hours to investigate the anti-cancer activity
 Absorbance of each well was measured a 540 nm with
an enzyme-linked immuosorbent assay (ELISA) reader
(Sunnyvale, CA, USA)
 Then, the cells were harvested and lysed, followed by
flow cytometry analysis to measure the mitochondrial
membrane potential and ROS generation.
 Various analyses such like Western blot, colorimetric
assay were performed.
 Significant difference by ANOVA with p<0.05
Park C, Lee WS, Go S, Nagappan A et al. Morin, a Flavonoid from Moraceae, Induces Apoptosis by Induction of
BAD Protein in Human Leukemic Cells. Int. J. Mol. Sci. 2015, 16, 645-659; doi:10.3390/ijms16010645.

19.  U937 cells were most sensitive to morin
 Morin induced caspase-dependent apoptosis
through an intrinsic pathway by up-regulation of
BAD proteins in U937 cells.
 The maximum concentration used in the study is 2-5
folds higher than other studies investigating its
antitumor effect.
 Morin also performed activities leading to apoptosis
in human leukemia HL-60 cells
 1) promoted ROS and Ca2+ productions,
 2) disruptions of mitochondria membrane potential, and
 3) activated caspase-3 and caspase-9
 In conclusion, morin might be useful in the treatment
of human hematopoietic cancer cells.
Park C, Lee WS, Go S, Nagappan A et al. Morin, a Flavonoid from Moraceae, Induces Apoptosis by Induction of
BAD Protein in Human Leukemic Cells. Int. J. Mol. Sci. 2015, 16, 645-659; doi:10.3390/ijms16010645.

20. Miller et al.
Phytochemicals and Cancer Risk: A
Review of the Epidemiological
Evidence

21.  Conducted a systematic review, includes a total of 96 publications, to
investigate the associations between phytochemicals and cancer risk.
 Inclusion criteria:
 1) prospective cohort study design;
 2) human population;
 3) outcome of primary cancer;
 4) serum or plasma marker, urinary metabolite, or dietary intake captured; and
 5) phytochemicals, whether dietary intake, plasma, serum, or urine were
quantified.
 Exclusion criteria:
 1) case-control study design;
 2) outcome of metastasis, secondary cancers, recurrence, or mortality;
 3) outcome of nonmelanoma skin cancer;
 4) only β-carotene or other vitamins or minerals examined;
 5) only food examined, rather than specific phytochemicals;
 6) animal and cell culture models; and
 7) only intermediate makers used as outcome.
Miller PE, Snyder DC. Phytochemicals and cancer risk: a review of the epidemiological evidence. Nutrition in
Clinical Practice. 2012; 27 (5): 599-612. DOI: 10.1177/0884533612456043.

22.  However, studies focusing on β-carotene alone are
also excluded due to its extensiveness in current
literatures. Thus, no randomized controlled trials
(RCTs) are included in this review.
Miller PE, Snyder DC. Phytochemicals and cancer risk: a review of the epidemiological evidence. Nutrition in
Clinical Practice. 2012; 27 (5): 599-612. DOI: 10.1177/0884533612456043.

23.  Carotenoids:
 55 studies are examined; the most commonly studied carotenes are
α-carotene, β-carotene, and lycopene for their antioxidant
properties which is considered the main mechanism for cancer
prevention.
 Other mechanisms include their ability to modulate intercellular
communication via gap junctions, alter intracellular signaling
pathways, and enhance immune function.
 2 studies demonstrated an inverse relationship among higher level of
β-carotene with renal cancer cells, while 1 study found a null
association .
 4 studies reported an inverse relationship among β-cryptoxanthin and
lung cancer while 2 other studies fun null associations.
 No significance reported for most other carotenoids and cancer site
studies.
 But, longer duration of β-carotene supplementation may increase lung
cancer risk .
Miller PE, Snyder DC. Phytochemicals and cancer risk: a review of the epidemiological evidence. Nutrition in
Clinical Practice. 2012; 27 (5): 599-612. DOI: 10.1177/0884533612456043.

24.  Phytosterols: only 1 epidemiological study examining
phytosterol and no effect on cancer risk with greater
intake, despite the promising results shown in animal and
cell culture studies.
 Isothiocyanates: 4 out of 5 studies reviewed have shown a
prospective effect of higher levels of Isothiocyanates.
 Chlorophyll: although animal and cell culture studies have
identified the plausible mechanism of chlorophyll and
reduced cancer risk, the only epidemiological study did not
suggest a significant relationship among them.
 Phytoestrogens: 39 studies are examined. Greater levels
of total flavonoid or specific types of flavonoids are found
to be inversely associated with lung, breast , stomach,
prostate, pancreatic, ovarian, and/or colorectal cancers .
 Most consistent association is found with lung cancer.
Miller PE, Snyder DC. Phytochemicals and cancer risk: a review of the epidemiological evidence. Nutrition in
Clinical Practice. 2012; 27 (5): 599-612. DOI: 10.1177/0884533612456043.

25.  In summary, an isolated study for any phytochemicals is
limited due to their synergetic actions in cancer risk
reduction, whether among other phytochemicals or dietary
nutrients.
 10 studies reported an increase cancer risk with higher
dietary intakes or serum, plasma, or urine metabolite levels
of certain phytochemicals.
 There is insufficient evidence to recommend a single
phytochemical supplementation to reduce cancer risk.
Miller PE, Snyder DC. Phytochemicals and cancer risk: a review of the epidemiological evidence. Nutrition in
Clinical Practice. 2012; 27 (5): 599-612. DOI: 10.1177/0884533612456043.

26. Take Home Message
 Phytochemicals, such as phenols and anthocyanin (from apples and
berries) have protective features against growth of cancer cells, but
the quantity and effectiveness in humans are still uncertain.
 Rossi et al. reviewed a number of phytochemicals commonly found in
beverages we drink and their chemopreventive properties. Since
there is no existing chemopreventive agent on the market, drinking
beverages rich in phytochemicals, namely EGCG in green tea, cocoa
in chocolates, caffeine in coffee, may be “an easy way to drink our
prevention.”
 Majority of the studies are done in animals and cell cultures, the
effects of phytochemicals on cancer prevention or inhibition are
based on targeting the type of cells, cell signaling, cell growth, etc.
without interference of any other metabolic activities those are taking
place constantly in a human body.
 Up to this date, there is insufficient evidence to recommend a
single phytochemical supplementation to reduce cancer risk.
Rossi T, Gallo C, Bassani B, Canali S, Albini A, Bruno A. Drink your prevention: beverages with cancer
preventive phytochemicals. Polskie Archiwum Medycyny Wewnetrznej. 2014; 124 (12): 713-719.