TY - JOUR
T1 - New insights into the molecular and epigenetic effects of antitumor Pt(IV)-valproic acid conjugates in human ovarian cancer cells
AU - Novohradsky, Vojtech
AU - Zerzankova, Lenka
AU - Stepankova, Jana
AU - Vrana, Oldrich
AU - Raveendran, Raji
AU - Gibson, Dan
AU - Kasparkova, Jana
AU - Brabec, Viktor
N1 - Publisher Copyright:
© 2015 Elsevier Inc.All rights reserved.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
KW - Cellular accumulation
KW - Chromatin decondensation
KW - Cytotoxicity
KW - Glutathione
KW - Histone deacetylase inhibition
KW - Platinum-valproic acid conjugates
UR - http://www.scopus.com/inward/record.url?scp=84936756705&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2015.04.003
DO - 10.1016/j.bcp.2015.04.003
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C2 - 25888926
AN - SCOPUS:84936756705
SN - 0006-2952
VL - 95
SP - 133
EP - 144
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 3
ER -