Berberine-induced apoptosis in human glioblastoma T98G cells is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction

Biol Pharm Bull. 2010;33(10):1644-9. doi: 10.1248/bpb.33.1644.


Berberine has a wide range of biochemical and pharmacologic effects, including antitumor activity, but the mechanisms involved in berberine-induced apoptosis remain unclear. The purpose of the present study was to investigate the changes in oxidative stress and endoplasmic reticulum (ER)-related molecules, which are closely associated with cell death-signaling transduction pathways, in human glioblastoma T98G cells treated with berberine. Berberine significantly decreased the cell viability of T98G cells in a dose-dependent manner. Berberine increased the production of reactive oxygen species (ROS) and level of intracellular Ca(2+). Berberine induced ER stress as evidenced by the detection of ER stress-associated molecules such as phosphorylated protein kinase-like ER kinase, eukaryotic translation initiation factor-2α, glucose-regulated protein 78/immunoglobulin heavy chain-binding protein, and CCAAT/enhancer-binding protein (C/EBP)-homologous protein/growth arrest and DNA damage-inducible gene 153, which was associated with the activation of caspase-3. Furthermore, the administration of the antioxidants, N-acetylcysteine and glutathione, reversed berberine-induced apoptosis. Berberine also markedly enhanced apoptosis in T98G cells through the induction of a higher ratio of Bax/Bcl-2 proteins, disruption of the mitochondrial membrane potential, activation of caspase-9 and -3, and cleavage of the poly(ADP-ribose) polymerase (PARP). The inhibition of ER stress using salubrinal led to an increased the level of Bcl-2, whereas the level of Bax, cleavage of procaspase-9 and -3, and PARP were decreased when compared with cells treated with berberine alone, indicating that berberine-induced apoptosis is associated with mitochondrial dysfunction. These results demonstrate that berberine induces apoptosis via ER stress through the elevation of ROS and mitochondrial-dependent pathway in human glioblastoma T98G cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Antioxidants / pharmacology
  • Apoptosis / drug effects*
  • Berberine / pharmacology*
  • Berberine / therapeutic use
  • Calcium / metabolism
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cinnamates / pharmacology
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects*
  • Oxidative Stress / drug effects
  • Phytotherapy
  • Plant Extracts / pharmacology*
  • Plant Extracts / therapeutic use
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction / drug effects
  • Thiourea / analogs & derivatives
  • Thiourea / pharmacology
  • bcl-2-Associated X Protein / metabolism


  • Antineoplastic Agents, Phytogenic
  • Antioxidants
  • Cinnamates
  • Plant Extracts
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • bcl-2-Associated X Protein
  • salubrinal
  • Berberine
  • Poly(ADP-ribose) Polymerases
  • Caspase 3
  • Caspase 9
  • Thiourea
  • Calcium