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

J Agric Food Chem. 2018 Jul 11;66(27):7054-7064. doi: 10.1021/acs.jafc.8b02458. Epub 2018 Jul 2.

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.

Keywords: 5-fluorouracil; HT-29 cells; colorectal cancer; intestinal mucositis; pomegranate peel ellagitannins.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects*
  • HT29 Cells
  • Humans
  • Hydrolyzable Tannins / administration & dosage
  • Hydrolyzable Tannins / chemistry
  • Hydrolyzable Tannins / pharmacology*
  • Lythraceae / chemistry*
  • Matrix Metalloproteinases / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mucositis / chemically induced
  • Mucositis / drug therapy*
  • Mucositis / metabolism
  • Rats
  • Reactive Oxygen Species / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Antioxidants
  • Hydrolyzable Tannins
  • Reactive Oxygen Species
  • Matrix Metalloproteinases
  • Fluorouracil