Anthracenedione derivative 1403P-3 induces apoptosis in KB and KBv200 cells via reactive oxygen species-independent mitochondrial pathway and death receptor pathway

Cancer Biol Ther. 2007 Sep;6(9):1413-21. doi: 10.4161/cbt.6.9.4543. Epub 2007 Jun 5.


Anthracenedione derivatives are potent cytotoxic agents to tumor cells. In this study, we investigated the anticancer activities of anthracenedione derivative 1403P-3 separated from the secondary metabolites of the mangrove endophytic fungus No. 1403. Our results demonstrated that 1403P-3 showed potent cytotoxicity not only to human epidermoid carcinoma drug-sensitive parental KB cells but also to multidrug resistant (MDR) KBv200 cells and the IC50 values were 19.66 and 19.27 muM, respectively. Further research indicated that 1403P-3 induced apoptosis in KB cells and KBv200 cells confirmed by Hoechst 33258 staining, detection of DNA fragmentation and cleavage of poly (ADP-ribose) polymerase (PARP). Furthermore, apoptosis triggered by 1403P-3 was characterized by the loss of mitochondrial membrane potential (DeltaPsi(m)), release of cytochrome c, cleavage of Bid, and activation of caspases-2, -3, -7, -8 and -9. Z-IETD-FMK, caspase-8 inhibitor could inhibit the activation of caspase-2 and cleavage of Bid induced by 1403P-3. However, activation of caspase-9 and cleavage of PARP caused by 1403P-3 were not inhibited by Z-IETD-FMK. Additionally, 1403P-3 did not influence the expression level of Bcl-2 and Bax. It is noteworthy that 1403P-3 decreased the generation of reactive oxygen species (ROS) in KB cells and KBv200 cells. DNA binding assay exhibited that apoptosis induced by 1403P-3 was not involved in intercalating to DNA. In summary, 1403P-3 induced apoptosis of KB cells and KBv200 cells through mitochondrial pathway and death receptor pathway. Furthermore, the mitochondrial pathway was independent of reactive oxygen species and activation of caspase-8.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthraquinones / chemistry*
  • Anthraquinones / pharmacology
  • Apoptosis
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • DNA Fragmentation
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Membrane Potentials
  • Mitochondria / metabolism*
  • Models, Biological
  • Reactive Oxygen Species*
  • Receptors, Death Domain / metabolism*


  • 1403P-3 compound
  • Anthraquinones
  • BH3 Interacting Domain Death Agonist Protein
  • Enzyme Inhibitors
  • Reactive Oxygen Species
  • Receptors, Death Domain
  • Caspases