Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78

Br J Cancer. 2013 Jul 23;109(2):433-43. doi: 10.1038/bjc.2013.325. Epub 2013 Jun 27.


Background: Glucose regulated protein 78 (GRP78) functions as a sensor of endoplasmic reticulum (ER) stress. The aim of this study was to test the hypothesis that molecules that bind to GRP78 induce the unfolded protein response (UPR) and enhance cell death in combination with ER stress inducers.

Methods: Differential scanning calorimetry (DSC), measurement of cell death by flow cytometry and the induction of ER stress markers using western blotting.

Results: Epigallocatechin gallate (EGCG), a flavonoid component of Green Tea Camellia sinensis, and honokiol (HNK), a Magnolia grandiflora derivative, bind to unfolded conformations of the GRP78 ATPase domain. Epigallocatechin gallate and HNK induced death in six neuroectodermal tumour cell lines tested. Levels of death to HNK were twice that for EGCG; half-maximal effective doses were similar but EGCG sensitivity varied more widely between cell types. Honokiol induced ER stress and UPR as predicted from its ability to interact with GRP78, but EGCG was less effective. With respect to cell death, HNK had synergistic effects on melanoma and glioblastoma cells with the ER stress inducers fenretinide or bortezomib, but only additive (fenretinide) or inhibitory (bortezomib) effects on neuroblastoma cells.

Conclusion: Honokiol induces apoptosis due to ER stress from an interaction with GRP78. The data are consistent with DSC results that suggest that HNK binds to GRP78 more effectively than EGCG. Therefore, HNK may warrant development as an antitumour drug.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / metabolism
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Apoptosis / drug effects*
  • Biphenyl Compounds / metabolism
  • Biphenyl Compounds / therapeutic use*
  • Catechin / analogs & derivatives*
  • Catechin / metabolism
  • Catechin / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / drug effects
  • Heat-Shock Proteins / antagonists & inhibitors
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Lignans / metabolism
  • Lignans / therapeutic use*
  • Molecular Targeted Therapy
  • Molecular Weight
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Protein Binding / drug effects


  • Antineoplastic Agents, Phytogenic
  • Biphenyl Compounds
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Lignans
  • honokiol
  • Catechin
  • epigallocatechin gallate