Induction of cell cycle arrest and DNA damage by the HDAC inhibitor panobinostat (LBH589) and the lipid peroxidation end product 4-hydroxynonenal in prostate cancer cells

Piergiorgio Pettazzoni, Stefania Pizzimenti, Cristina Toaldo, Paula Sotomayor, Luigina Tagliavacca, Song Liu, Dan Wang, Rosalba Minelli, Leigh Ellis, Peter Atadja, Eric Ciamporcero, Mario Umberto Dianzani, Giuseppina Barrera, Roberto Pili

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Histone deacetylase inhibitors (HDACIs) are promising antineoplastic agents for the treatment of cancer. Here we report that the lipid peroxidation end product 4-hydroxynonenal (HNE) significantly potentiates the anti-tumor effects of the HDAC inhibitor panobinostat (LBH589) in the PC3 prostate cancer cell model. Panobinostat and HNE inhibited proliferation of PC3 cells and the combination of the two agents resulted in a significant combined effect. Cell cycle analysis revealed that both single agents and, to a greater extent, their combined treatment induced G2/M arrest, but cell death occurred in the combined treatment only. Furthermore, HNE and, to a greater extent, the combined treatment induced dephosphorylation of Cdc2 leading to progression into mitosis as confirmed by α-tubulin/DAPI staining and phospho-histone H3 (Ser10) analysis. To evaluate possible induction of DNA damage we utilized the marker phosphorylated histone H2A.X. Results showed that the combination of panobinostat and HNE induced significant DNA damage concomitant with the mitotic arrest. Then, by using androgen receptor (AR)-expressing PC3 cells we observed that the responsiveness to HNE and panobinostat was independent of the expression of functional AR. Taken together, our data suggest that HNE potentiates the antitumoral effect of the HDACI panobinostat in prostate cancer cells.

Original languageEnglish (US)
Pages (from-to)313-322
Number of pages10
JournalFree Radical Biology and Medicine
Volume50
Issue number2
DOIs
StatePublished - Jan 15 2011
Externally publishedYes

Keywords

  • Androgen receptor
  • DNA damage
  • Free radicals
  • HNE
  • Mitotic arrest
  • Panobinostat
  • Prostate cancer

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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  • Cite this

    Pettazzoni, P., Pizzimenti, S., Toaldo, C., Sotomayor, P., Tagliavacca, L., Liu, S., Wang, D., Minelli, R., Ellis, L., Atadja, P., Ciamporcero, E., Dianzani, M. U., Barrera, G., & Pili, R. (2011). Induction of cell cycle arrest and DNA damage by the HDAC inhibitor panobinostat (LBH589) and the lipid peroxidation end product 4-hydroxynonenal in prostate cancer cells. Free Radical Biology and Medicine, 50(2), 313-322. https://doi.org/10.1016/j.freeradbiomed.2010.11.011