Ellagic Acid Enhances the Antitumor Efficacy of Bevacizumab in an In Vitro Glioblastoma Model

World Neurosurg. 2019 Dec;132:e59-e65. doi: 10.1016/j.wneu.2019.08.257. Epub 2019 Sep 10.


Background: The anticarcinogenic effect of ellagic acid (EA), a natural phenol of fruits and vegetables, has been investigated in several types of tumors. The combined effect of EA with bevacizumab (BEV), a common drug used in treatment of recurrent glioma, on glioblastoma has not been reported. This study observed the combined effect of EA with BEV on the expression profile of the C6 glioma cell line.

Methods: Rat C6 glioma cells were treated with EA at 100 μmol/L concentration in combination with BEV at 100 ng/mL concentration for 24, 48, and 72 hours. Cell proliferation was detected by 5-bromo-2'-deoxyuridine immunohistochemistry, and p53 and caspase-3 protein levels were determined by immunohistochemistry and assessed by the H-Score. Expression profiles for P-glycoprotein (MDR1), O6-methylguanine DNA methyltransferase (MGMT), caspase-3, and p53 related proteins were detected by reverse transcriptase polymerase chain reaction after EA treatment with or without BEV.

Results: EA combined with BEV conspicuously reduced the cell viability of C6 glioma cells for all incubation times. EA significantly downregulated expression of MGMT regardless of combination with BEV even in the early hours after treatment. Combined EA and BEV reduced MDR1 expression only at 72 hours. EA affected the apoptotic proteins of p53 and caspase-3 at protein level in a time-dependent manner, but not at gene level.

Conclusions: This study suggests successful antiproliferative efficacy of EA combined with BEV, probably through inhibition of MGMT expression and time-dependent inhibition of MDR1. EA combined with BEV may be an alternative treatment for drug-resistant gliomas.

Keywords: Cancer therapy; Ellagic acid; Glioblastoma; Temozolomide.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents, Immunological / pharmacology*
  • Apoptosis / drug effects
  • Bevacizumab / pharmacology*
  • Brain Neoplasms / drug therapy*
  • Bromodeoxyuridine / pharmacology
  • Cell Line, Tumor
  • DNA Repair / drug effects
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Ellagic Acid / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / drug therapy*
  • Rats


  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents, Immunological
  • Ellagic Acid
  • Bevacizumab
  • Bromodeoxyuridine