Glaucocalyxin A induces apoptosis in human leukemia HL-60 cells through mitochondria-mediated death pathway

Toxicol In Vitro. 2011 Feb;25(1):51-63. doi: 10.1016/j.tiv.2010.09.006. Epub 2010 Sep 17.

Abstract

Glaucocalyxin A (GLA) is a biologically active ent-kauranoid diterpenoid isolated from Rabdosia japonica var. glaucocalyx, a traditional Chinese medicinal herb, which has been shown to inhibit tumor cell proliferation. However, the mechanism underlying GLA-induced cytotoxicity remains unclear. In this study, we focused on the effect of GLA induction on apoptosis, the mitochondria-mediated death pathway and the accumulation of reactive oxygen species (ROS) in human leukemia cells (HL-60). GLA could induce a dose-dependent apoptosis in HL-60 cells as characterized by cell morphology, DNA fragmentation, activation of caspase-3, -9 and an increased expression ratio of Bax/Bcl-2. The mitochondrial membrane potential (Δψ(m)) loss and cytochrome c release from mitochondria to cytosol were observed during the induction. Moreover, GLA caused a time- and dose-dependent elevation of intracellular ROS level in HL-60 cells, and N-acetyl-l-cysteine (NAC, a well-known antioxidant) could block GLA-induced ROS generation and apoptosis. These data suggest that GLA induces apoptosis in HL-60 cells through ROS-dependent mitochondrial dysfunction pathway.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / antagonists & inhibitors
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antioxidants / pharmacology
  • Apoptosis / drug effects*
  • Biomarkers / metabolism
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Fragmentation / drug effects
  • Diterpenes, Kaurane / antagonists & inhibitors
  • Diterpenes, Kaurane / pharmacology
  • Drugs, Chinese Herbal / pharmacology*
  • G1 Phase / drug effects
  • HL-60 Cells
  • Humans
  • Inhibitory Concentration 50
  • Leukemia / drug therapy*
  • Leukemia / metabolism
  • Leukemia / pathology
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects*
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents, Phytogenic
  • Antioxidants
  • Biomarkers
  • Diterpenes, Kaurane
  • Drugs, Chinese Herbal
  • Reactive Oxygen Species
  • glaucocalyxin A
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9