title: New insights into the molecular and epigenetic effects of antitumor Pt(IV)-valproic acid conjugates in human ovarian cancer cells.
abstract: Substitutionally inert Pt(IV) prodrugs, combining bioactive axial ligands with Pt(IV) derivatives of antitumor Pt(II) compounds, represent a new generation of anticancer drugs. The rationale behind these prodrugs is to release, by reductive elimination inside the cancer cell, an active Pt(II) drug which binds nuclear DNA as well as bioactive ligands that may potentiate toxic effects of the Pt(II) drugs by an independent pathway. Platinum prodrugs, such as Pt(IV) derivatives of cisplatin containing axial valproic acid (VPA) ligands, destroy cancer cells with greater efficacy than conventional cisplatin. These axial ligands were chosen because VPA inhibits histone deacetylase (HDAC) activity, thereby decondensing chromatin and subsequently increasing the accessibility of DNA within chromatin to DNA-binding agents. We examined the mechanism of cytotoxic activity of Pt(IV) derivatives of cisplatin with VPA axial ligands. Particular attention was paid to the role of the VPA ligand in these Pt(IV) prodrugs in the mechanism underlying their toxic effects in human ovarian tumor cells. We demonstrate that (i) treatment of the cells with these prodrugs resulted in enhanced histone H3 acetylation and decondensation of heterochromatin markedly more effectively than free VPA; (ii) of the total Pt inside the cells, a considerably higher fraction of Pt from the Pt(IV)-VPA conjugates is bound to DNA than from the conjugates with biologically inactive ligands. The results indicate that the enhanced cytotoxicity of the Pt(IV)-VPA conjugates is a consequence of several processes involving enhanced cellular accumulation, downregulation of HDACs and yet other biochemical processes (not involving HDACs) which may potentiate antitumor effects.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Novohradsky
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Zerzankova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Stepankova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
authors.forename: Oldrich
authors.initials: O
authors.lastname: Vrana
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem 91120, Israel.
authors.forename: Raji
authors.initials: R
authors.lastname: Raveendran
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem 91120, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Gibson
authors.affiliation: Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic. Electronic address: brabec@ibp.cz.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014635:Valproic Acid / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006657:Histones; D009944:Organoplatinum Compounds; D014635:Valproic Acid; D006655:Histone Deacetylases; D005978:Glutathione
keywords: Cellular accumulation; Chromatin decondensation; Cytotoxicity; Glutathione; Histone deacetylase inhibition; Platinum-valproic acid conjugates