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, Kargo Kar Ho Lam, Yi Bin Feng, Kai Xu, Cho Wing SZE, Sydney Chi Wai Tang, George Pak Hen Leung, Calvin Kai Fai Lee, Jun Shi, Zhijun YANG, Sheng Tao Li, Zhang Jin Zhang*, Kalin Yan Bo Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Worldwide, colorectal cancer (CRC) is a deleterious disease causing millions of death annually. 5-Fluorouracil (5-FU) is a first-line chemotherapy for CRC, but chemoresistance and gastrointestinal mucositis limit its efficacy. Polyphenol-rich foods are increasingly popular due to their potential beneficial roles in preventing and treating cancer. Ellagitannins are a group of phenolic compounds commonly found in pomegranate, strawberries, raspberries, etc. The objective of this study was to explore whether ellagitannins from pomegranate (PETs) could ameliorate 5-FU-induced intestinal mucositis and enhance the drug's efficacy against CRC. The results showed that PETs (100 mg/kg) counteracted 5-FU-induced intestinal mucositis in rats. The number of apoptotic cells per crypt was reduced from 1.50 ± 0.21 to 0.85 ± 0.18 (P < 0.05). Moreover, PETs induced HT-29 CRC cell death through intrinsic apoptosis, as demonstrated by dissipation of mitochondrial membrane potential, increased Bax-to-Bcl-2 ratio, and cleavage of caspase 9 and caspase 3. PETs and 5-FU combination treatments exhibited synergistic cytotoxicity against HT-29 cells with a weighted combination index of 0.3494. PETs (80 μg/mL) and 5-FU (40 μg/mL) treatments for 48 h induced 14.03 ± 0.76% and 16.42 ± 1.15% of HT-29 cells to undergo apoptosis, while the combination treatment further increased apoptosis of cells to 34.00 ± 1.54% (P < 0.05). Combination treatment of the cells also enhanced S phase cell cycle arrest as compared with PETs or 5-FU monotherapy (P < 0.05). These results suggest that dietary ellagitannins from pomegranate could alleviate intestinal mucositis in rats induced by 5-FU while enhancing its toxicity against HT-29 cells through potentiation of apoptosis and cell cycle arrest.

Original languageEnglish
Pages (from-to)7054-7064
Number of pages11
JournalJournal of Agricultural and Food Chemistry
Volume66
Issue number27
DOIs
Publication statusPublished - 11 Jul 2018

Scopus Subject Areas

  • Chemistry(all)
  • Agricultural and Biological Sciences(all)

User-Defined Keywords

  • 5-fluorouracil
  • colorectal cancer
  • HT-29 cells
  • intestinal mucositis
  • pomegranate peel ellagitannins

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