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Bioactive Constituents, Metabolites, and Functions
Ellagitannins from pomegranate ameliorates 5-fluorouracil-induced intestinal mucositis in rats while enhancing its chemotoxicity against HT-29 colorectal cancer cells through intrinsic apoptosis induction Xiao-Xin Chen, Kar Ho Lam, Yibin Feng, Kai Xu, Stephen C.W. Sze, Chi Wai Tang, George P.H. Leung, Calvin Kai-Fai Lee, Jun Shi, Zhijun Yang, Sheng-Tao Li, Zhang-Jin Zhang, and Yanbo Zhang J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b02458 • Publication Date (Web): 19 Jun 2018 Downloaded from http://pubs.acs.org on June 21, 2018
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Journal of Agricultural and Food Chemistry
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Ellagitannins from pomegranate ameliorates 5-fluorouracil-induced intestinal mucositis
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in rats while enhancing its chemotoxicity against HT-29 colorectal cancer cells through
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intrinsic apoptosis induction
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Xiao-Xin Chen1, Kargo Kar-Ho Lam1, Yi-Bin Feng1, Kai Xu1, Stephen Cho-Wing Sze2,
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Sydney Chi-Wai Tang3, George Pak-Hen Leung4, Calvin Kai-Fai Lee5, Jun Shi1, Zhi-Jun
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Yang6, Sheng-Tao Li1, Zhang-Jin Zhang1*, Kalin Yan-Bo Zhang1**
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1
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Pharmacy,
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University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong;
School of Chinese Medicine, 3Department of medicine, 4Department of Pharmacology and 5
Department of Obstetrics and Gynaecology, LKS Faculty of Medicine,
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2
Department of Biology, 6School of Chinese Medicine, Hong Kong Baptist University,
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Kowloon Tong, Kowloon, Hong Kong
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*Correspondence: Tel: +852 39176445; Fax: +852 28725476.
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**Correspondence: Tel: +852 25890481; Fax: +852 28725476.
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E-mail:
[email protected] (Z.J. Zhang);
[email protected] (K. Y. Zhang).
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Abbreviations:
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AAE/g dw: ascorbic acid equivalent/g dry weight; CI: combination index; CIwt: weighted average; CRC: colorectal cancer; DCF-DA: 2’,7’-dichlorofluorescin diacetate; DMEM: Dulbecco’s Modified Eagle Medium; DPPH: 2,2-diphenyl-1-picrylhydrazyl; Dm: the dose that produces 50 percent effect; DRI: drug reduction index; Fa: Factional affected; FBS: fetal bovine serum; Fu: Factional unaffected; 5-FU: 5-fluorouracil; GAE/g dw: gallic acid equivalent/g dry weight; HPLC-DAD-ESI-MS/MS: high performance liquid chromatography/diode array detector coupled with electrospray ionization tandem mass spectrometry; factor-related apoptosis-inducing ligand;
IC50:
the
dose
that inhibit
TRAIL: tumor necrosis
50 percent
activity;
JC-1:
tetraethylbenzimidazolylcarbocyanine iodide; ROS: reactive oxygen species; MMP: mitochondrial membrane potential; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS: phosphate buffer solution; PI: propidium iodide; r value: the linear correlation coefficient of the median-effect plot; RPMI: roswell park memorial institute; PETs: ellagitannins from pomegranate peel; TP: total phenolics;
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1 ACS Paragon Plus Environment
Journal of Agricultural and Food Chemistry
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Graphical Abstract
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2 ACS Paragon Plus Environment
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Journal of Agricultural and Food Chemistry
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Abstract
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Worldwide, colorectal cancer (CRC) is a deleterious disease causing millions of death
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annually. 5-Fluorouracil (5-FU) is a first-line chemotherapy for CRC, but chemoresistance
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and gastrointestinal mucositis limit its efficacy. Polyphenol-rich foods are increasingly
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popular due to their potential beneficial role in cancer. Ellagitannins is a group of phenolic
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compounds commonly found in pomegranate, strawberries, raspberries, etc. The objective of
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this study was to explore whether ellagitannins from pomegranate (PETs) could ameliorate
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5-FU-induced intestinal mucositis and enhance its efficacy against CRC. The results showed
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that PETs (100 mg/kg) counteracted 5-FU-induced intestinal mucositis in rats. The number of
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apoptotic cells per crypt was reduced from 1.50±0.21 to 0.85±0.18 (P
