title: 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.
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.
authors.affiliation: Department of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, Turin, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Pettazzoni
authors.forename: Stefania
authors.initials: S
authors.lastname: Pizzimenti
authors.forename: Cristina
authors.initials: C
authors.lastname: Toaldo
authors.forename: Paula
authors.initials: P
authors.lastname: Sotomayor
authors.forename: Luigina
authors.initials: L
authors.lastname: Tagliavacca
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Rosalba
authors.initials: R
authors.lastname: Minelli
authors.forename: Leigh
authors.initials: L
authors.lastname: Ellis
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Eric
authors.initials: E
authors.lastname: Ciamporcero
authors.forename: Mario Umberto
authors.initials: MU
authors.lastname: Dianzani
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Barrera
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
mesh_terms: D000107:Acetylation; D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005978:Glutathione / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D000077767:Panobinostat; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D011944:Receptors, Androgen; D000077767:Panobinostat; D005978:Glutathione; C027576:4-hydroxy-2-nonenal