Cancer Therapies
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485417
research-article2013
Article
Abstract
Objectives. The aims of this study were to determine the effect of conjugated linoleic acid (CLA) supplementation on
inflammatory factors and matrix metalloproteinase (MMP) enzymes in rectal cancer patients undergoing chemoradiothetrapy.
Method and Material. In this randomized, double-blind, placebo-controlled pilot study, 34 volunteer patients with rectal
cancer undergoing chemoradiotherapy assigned into the CLA group (n = 16), receiving 3 g CLA/d, and placebo group (n =
18) receiving placebo capsules (sunflower oil) for 6 weeks. The supplementation began 1 week before starting RT (loading
period) and continued every day during treatment. Before and after intervention, serum tumor necrosis factor (TNF-),
interleukin 1 (IL-1), IL-6, MMP-2, MMP-9, and high-sensitivity C-reactive protein (hsCRP) were measured by enzymelinked immunosorbent assay (ELISA) kits and immunoturbidimetric method, respectively. Independent t tests and paired
t tests were used to compare parameters between and within groups, respectively. Results. In the CLA group, the mean
serum TNF-, IL-1, hsCRP, MMP-9, and MMP-2 levels reduced insignificantly. However, significant changes in TNF-
(P = 0.04), hsCRP (P = 0.03), and MMP-9 (P = 0.04) concentrations were observed in the CLA group when compared with
the placebo group. The mean serum IL-6 level remained unchanged in the CLA group but increased remarkably in the
placebo group. Conclusion. According to our results, CLA supplementation improved inflammatory factors, MMP-2, and
MMP-9 as biomarkers of angiogenesis and tumor invasion. It seems that CLA may provide new complementary treatment
by reducing tumor invasion and resistance to cancer treatment in patients with rectal cancer.
Keywords
rectal cancer, chemoradiotherapy, conjugated linoleic acid supplementation, inflammatory factors, matrix metalloproteinase
enzymes1
Introduction
Colorectal cancer is one of the most prevalent cancers in the
world, and it is the third most common cancer in both men
and women.1 Surgery and preoperative chemoradiotherapy
(CRT) or postoperative CRT are the main treatments for
rectal cancer.1 In most oncology departments, preoperative
chemoradiation is now the current standard of care for
locally advanced operable rectal cancer.2
It is now known that exposure to clinically relevant
doses of ionizing radiation stimulates various biological
responses at the cell and tissue levels through the early
activation of cytokine cascades.3 Increases in proinflammatory cytokines such as tumor necrosis factor (TNF),interleukin 1 (IL-1), IL-6, and IL-8 as a result of cancer
Corresponding Author:
Elnaz Faramarzi, Nutrition Research Center, Tabriz University of
Medical Sciences, Tabrzi 51677, Iran.
Email: elnazfaramarzi849@gmail.com
497
Mohammad-zadeh et al
activities for the prevention of radiotherapy (RT) failure
and tumor recurrence and the enhancement of tumor radiosensitivity while reducing tumor vascularization and cell
invasion.4-6
Conjugated linoleic acids (CLAs), which represent a
heterogeneous group of positional and geometric isomers
of linoleic acid are found mainly in foods derived from
ruminant animals (such as dairy products and meats).7
CLA consists of a mixture of geometric and positional isomers (cis or trans double-bond positioning at ([7,9],
[8,10], [9,11], [10,12], or [11,13]). The most abundant isomer in dietary sources is cis-9,trans-11-CLA (more than
75%-90% of total CLA).7 The trans-10,cis-12 is the other
main isomer, which represents 1% to 10% of total CLA
from food sources.8 According to findings from animal
and human studies, CLA has beneficial effects on cancer,
inflammation, body composition, diabetes and cardiovascular disease.9 Nowadays, most research is focused on
CLA because of its anti-inflammatory and anticancer
properties. The findings of in vitro and in vivo studies
indicate that CLA has anti-inflammatory effects, for
example, reducing colonic inflammation10 and modulating
the production of cytokines and prostaglandins.11,12 In
humans, CLA has modest anti-inflammatory effects and
improves immune function.13 The results of another clinical trial showed that 6 g of CLA mixture per day in patients
with Crohns disease suppressed the production of proinflammatory cytokines.14 Furthermore, results from animal
studies showed that CLA supplementation inhibited colon
cancer incidence, progression, and metastasis.15-17 Also,
several in vitro studies have demonstrated that CLA supplementation inhibited metastasis and immigration of
human colon cancer cell line Colo32018 and SW480 cells17
by different mechanisms. Recently, Grdzka et al19
reported that C9,t11-CLA increased sensitivity of HT-29
cells to X radiation. Also, Cho et al20 found that t10,c12CLA isomer inhibited HT-29 cells growth via the induction of G1 cell cycle arrest. The results of another
study indicated that the t10,c12 isomer has more inhibitory effects than the c9,t11 isomer on colorectal cancer
proliferation.21
Anti-inflammatory properties of CLA have been investigated less in human studies, and to the best of our knowledge, there is no published article about the effect of mixed
CLA supplementation in cancer patients. Therefore, we
evaluated the effect of CLA supplementation on serum
inflammatory factors and matrix metalloproteinase (MMP)
enzymes as biomarkers of angiogenesis and tumor invasion,
and serum liver enzyme levels in rectal cancer patients
undergoing CRT.
498
62.4 15.6
58.05 16.4
8 (53.38%)
7 (46.7%)
10 (58.8%)
7 (41.2%)
6 (40%)
9 (60%)
161.7 8.7
66.1 11.2
25.3 4.2
6 (35.3%)
11 (64.7%)
156.5 22.9
64.8 10.1
24.6 3.7
P
0.44a
0.75c
0.78c
0.42a
0.73a
0.61a
Independent t test.
Based on TNM staging.
c 2
test.
b
Statistical Analysis
The data were analyzed using Statistical Package for the
Social Sciences (SPSS, version 11.5, Chicago, IL).We used
the independent t test on quantitative parameters and the 2
test on qualitative variables (gender and stage of disease) to
determine whether baseline characteristics differed between
the CLA and placebo groups. Because all quantitative parameters had normal distributions according to the KolmogorovSmirnov test, data were presented as mean standard
deviation. The paired t test was used to compare serum biochemical factors at the end of the study with baseline values.
An independent t test was performed to compare changes
(from preintervention to the end of study) of biochemical factors between the 2 groups. An analysis of covariance test was
used to adjust the effect of confounding factors (baseline values of biochemical parameters). A P value of less than 0.05
was considered statistically significant.
Results
In this study, 34 patients were recruited. In the CLA group,
1 patient consumed less than 90% of the planned number of
capsules because of forgetting to take CLA capsules regularly and was excluded from the study. In the placebo group,
one patient was hospitalized and excluded from the study.
Finally, statistical analysis was performed on 32 patients
(CLA group, n = 15; placebo group, n = 17). There were no
significant differences in baseline characteristics between
the 2 groups, as presented in Table 1. The mean biochemical
factors and comparison of changes between the study
groups before and after intervention are indicated in Tables
2 and 3, respectively. Only the baseline values of MMP-9
were significantly (P = 0.01) different from those of the
control group (Table 2).
After intervention, the mean serum TNF- and IL-1
levels did not change significantly within each group (Table
Discussion
A variety of cytokines (TNF-, Il-6, Il-1) and other factors
such as NF-B and COX2 are involved in the incidence of
inflammation resulting from cancer and cancer treatments.3,17 It has been reported that inflammation plays an
important role in progression, invasion, metastasis, chemoresistance, and radioresistance of colorectal cancer.23,24
Therefore, today, many studies are focused on the development of new anti-inflammatory therapeutic approaches
for blocking their synthesis or action,25 especially by
499
Mohammad-zadeh et al
Table 2. The Mean Serum Biochemical Factors Before and After Intervention in Both Supplemented and Placebo Groups.a.
CLA Group (n = 15)
TNF- (pg/mL)
IL-1 (pg/mL)
IL-6 (pg/mL)
hsCRP (mg/L)
MMP-9 (ng/mL)
MMP-2 (ng/mL)
ALT (U/L)
AST (U/L)
ALP (U/L)
Before
After
Pb
Before
After
55.6 8.67
45.4 5.18
6.1 3.9
2.5 2.1
578.01 237.14c
21.28 16.17
15.1 11.4
15.6 3.2
218.7 55.16
54.5 3.06
45.1 4.84
6.5 4.5
1.7 1.5
499.8 297.3
21.19 4.69
15.3 6.0
15.1 5.34
190.4 36.95
0.68
0.81
0.89
0.45
0.31
0.98
0.90
0.31
0.02
55.8 7.2
44.7 5.3
8.03 5.4
2.4 2.26
839.1 302.43
22.26 18.58
14.8 9.04
17.93 4.25
221.2 53.60
57.7 4.39
45.7 10.84
12.3 11.8
3.8 3.2
815.7 291.72
25.11 20.74
13.6 9.7
16.2 6.01
220.3 56.29
Pb
0.30
0.35
0.19
0.06
0.80
0.64
0.57
0.28
0.94
Abbreviations: CLA, conjugated linoleic acid; TNF-, tumor necrosis factor ; IL, interleukin 1; hsCRP, high-sensitivity C-reactive protein; MMP,
matrix metalloproteinase; ALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase.
a
Mean value standard deviation.
b
P, comparison within group by paired t test.
c
Baseline values were significantly different from that in the placebo group.
Pb
0.04
0.60
0.26
0.03
0.04
0.69
0.60
0.56
0.05
Abbreviations: CLA, conjugated linoleic acid; TNF-, tumor necrosis factor ; IL, interleukin 1; hsCRP, high-sensitivity C-reactive protein; MMP,
matrix metalloproteinase; ALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase.
a
ANCOVA was used to adjust baseline values of biochemical parameters; mean value (95% confidence interval).
b
P, comparison between groups by independent t test.
g/d for 12 weeks) in patients with Crohns disease suppressed the ability of peripheral blood T cells to produce
proinflammatory cytokines and decreased disease activity.
They concluded that CLA supplementation represents a new
complementary treatment for gut inflammation. Taking into
account the important role of inflammation in tumor formation and progression of colorectal cancer and the antiinflammatory and anti-carcinogenic properties of CLA, we
assumed that dietary CLA ameliorates inflammatory conditions and, therefore, it can prevent disease progression. In
support of this hypothesis, the result of our study showed
that 3 g/d CLA supplementation for 6 weeks in rectal cancer
patients undergoing CRT reduced TNF- levels significantly
as compared with the placebo group. To the best of our
knowledge, there is no published article about the effect of
CLA supplementation on inflammatory factors and MMP
enzymes in rectal cancer patients undergoing CRT.
500
501
Mohammad-zadeh et al
Moreover, CLA supplementation prevented the elevation of
IL-1 and IL-6 concentrations as biomarkers of inflammation when compared with the placebo group in rectal cancer
patients undergoing CRT.
Based on the results of previous animal studies and
the present study, it seems that CLA may provide a
new complementary treatment by reducing tumor invasion
and resistance to cancer treatment in patients with rectal
cancer. However, further studies with larger sample sizes
are needed to achieve more precise results. Moreover,
it would be worthwhile to study the effect of different
doses of oral CLA supplementation on the production of
inflammatory factors and the immune function in cancer
patients.
Acknowledgment
The authors are grateful for the financial support of the Nutrition
Research Center, Tabriz University of Medical Sciences. The
authors also are deeply indebted to all patients who participated in
this study.
Authors Note
This article was written based on a data set for the PhD thesis
(Elnaz Faramarzi) registered in Tabriz University of Medical
Sciences.
Funding
The authors disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: The
authors are grateful for the financial support of the Nutrition
Research Center, Tabriz University of Medical Sciences.
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