Pifithrin-alpha promotes p53-mediated apoptosis in JB6 cells

Mol Carcinog. 2003 Jul;37(3):138-48. doi: 10.1002/mc.10130.

Abstract

Recently, blockage of p53-dependent transcriptional activation and apoptosis by pifithrin-alpha (PFTalpha) has been reported to be useful for reducing the side effects of cancer therapy and the compound is thus thought to be a specific inhibitor of p53 [Komarov et al., Science 1999;285:1733-1737]. Here, we found that PFTalpha did not inhibit UVB- or doxorubicin (Dox)-stimulated p53-mediated transcriptional activation and apoptosis in JB6 cells. Instead, p53-dependent activation and apoptosis were not only induced by PFTalpha itself but were also enhanced by a combination of PFTalpha with UVB or Dox. Furthermore, PFTalpha-induced apoptosis was mediated through p53-dependent and -independent signaling pathways. Extracellular signal-regulated kinases and p38 kinase, but not c-jun N-terminal kinases (JNKs), were activated, and these activations were required for phosphorylation and accumulation of p53 in the cellular apoptotic response to PFTalpha. Thus, we conclude that PFTalpha is not a specific p53 inhibitor in JB6 cells but is a potential activator of p53-mediated signaling and apoptosis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / radiation effects
  • Benzothiazoles
  • Blotting, Western
  • Cells, Cultured
  • Doxorubicin / pharmacology
  • Gene Expression Regulation
  • Genes, Dominant
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Precipitin Tests
  • Signal Transduction / drug effects*
  • Signal Transduction / radiation effects
  • Skin / cytology
  • Skin / drug effects
  • Thiazoles / metabolism
  • Thiazoles / pharmacology*
  • Toluene / analogs & derivatives*
  • Toluene / metabolism
  • Toluene / pharmacology*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / radiation effects
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / metabolism*
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Antineoplastic Agents
  • Benzothiazoles
  • Thiazoles
  • Tumor Suppressor Protein p53
  • Toluene
  • Doxorubicin
  • pifithrin
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases