title: Antitumor platinum(IV) derivatives of oxaliplatin with axial valproato ligands.
abstract: We report new anticancer prodrugs, platinum(IV) derivatives of oxaliplatin conjugated with valproic acid (VPA), a well-known drug having histone deacetylase inhibitory activity. Like most platinum(IV) derivatives, the cytotoxicity of the conjugates was lower in cell culture than that of oxaliplatin, but greater than those of its Pt(IV) derivative containing biologically inactive axial ligands in several cancer cell lines. Notably, these conjugates display activity in both cisplatin sensitive- and resistant tumor cells capable of both markedly enhanced accumulation in tumor cells and acting in a dual threat manner, concurrently targeting histone deacetylase and genomic DNA. These results demonstrate the dual targeting strategy to be a valuable route to pursue in the design of platinum agents which may be more effective in cancer types that are typically resistant to therapy by conventional cisplatin. Moreover, platinum(IV) derivatives containing VPA axial ligands seem to be promising dual-targeting candidates for additional preclinical studies.
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic; Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
authors: Vojtech
authors: V
authors: Novohradsky
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
authors: Lenka
authors: L
authors: Zerzankova
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
authors: Jana
authors: J
authors: Stepankova
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
authors: Oldrich
authors: O
authors: Vrana
authors: Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem 91120, Israel.
authors: Raji
authors: R
authors: Raveendran
authors: Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem 91120, Israel.
authors: Dan
authors: D
authors: Gibson
authors: Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
authors: Jana
authors: J
authors: Kasparkova
authors: 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: Viktor
authors: V
authors: Brabec
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D000077150:Oxaliplatin
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D008024:Ligands; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin
keywords: Anticancer; Dual targeting; Histone deacetylase; Oxaliplatin; Platinum(IV) prodrugs; Valproic acid