TY - JOUR
T1 - 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
AU - Pettazzoni, Piergiorgio
AU - Pizzimenti, Stefania
AU - Toaldo, Cristina
AU - Sotomayor, Paula
AU - Tagliavacca, Luigina
AU - Liu, Song
AU - Wang, Dan
AU - Minelli, Rosalba
AU - Ellis, Leigh
AU - Atadja, Peter
AU - Ciamporcero, Eric
AU - Dianzani, Mario Umberto
AU - Barrera, Giuseppina
AU - Pili, Roberto
N1 - Funding Information:
This work was supported by Compagnia di San Paolo (MIUR-PRIN 2004 2004062075 to G.B.) and the National Cancer Institute (P50 CA58236 to R.P.).
PY - 2011/1/15
Y1 - 2011/1/15
N2 - 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.
AB - 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.
KW - Androgen receptor
KW - DNA damage
KW - Free radicals
KW - HNE
KW - Mitotic arrest
KW - Panobinostat
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=78651244903&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2010.11.011
DO - 10.1016/j.freeradbiomed.2010.11.011
M3 - Article
C2 - 21078383
AN - SCOPUS:78651244903
SN - 0891-5849
VL - 50
SP - 313
EP - 322
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 2
ER -