NDLI: Pt(iv) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action

Content Provider	Royal Society of Chemistry (RSC)
Author	Gandin, Valentina Gibson, Dan Stuchlikova, Olga Wexselblatt, Ezequiel Brabec, Viktor Novohradsky, Vojtech Raveendran, Raji Braude, Jeremy Phillip
Copyright Year	2016
Abstract	Our study demonstrates that Pt(IV) derivative of cisplatin, with two axial PhB ligands, ctc-[Pt(NH3)2(PhB)2Cl2], is a very potent cytotoxic agent against many different human cancer cell lines and is up to 100 fold more potent than cisplatin, and significantly more potent than the Pt(IV) derivatives of cisplatin with either two hydroxido, two acetato or two valproato ligands. The high potency of this compound (and some others) is due to several factors including enhanced internalization, probably driven by “synergistic accumulation” of both the Pt moiety and the phenylbutyrate, that correlates with enhanced DNA binding and cytotoxicity. ctc-[Pt(NH3)2(PhB)2Cl2] inhibits 60–70% HDAC activity in cancer cells, at levels below the IC50 values of PhB, suggesting synergism between Pt and PhB. Mechanistically, ctc-[Pt(NH3)2(PhB)2Cl2] induces activation of caspases (3 and 9) triggering apoptotic signaling via the mitochondrial pathway. Data also suggest that the antiproliferative effect of ctc-[Pt(NH3)2(PhB)2Cl2] may not depend of p53. Pt(IV) derivatives of cisplatin with either two axial PhB or valproate ligands are more potent than their oxaliplatin analogs. ctc-[Pt(NH3)2(PhB)2Cl2] is significantly more potent than its valproate analog ctc-[Pt(NH3)2(VPA)2Cl2]. These compounds combine multiple effects such as efficient uptake of both Pt and PhB with DNA binding, HDAC inhibition and activation of caspases to effectively kill cancer cells.
Starting Page	2381
Ending Page	2391
Page Count	11
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	7
Issue Number	3
Journal	Chemical Science
DOI	10.1039/c5sc04205d
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	Ammonia Oxaliplatin VPA DNA IC50 Cytotoxicity Cisplatin Cancer P53 Valproate
Content Type	Text
Resource Type	Article
Subject	Chemistry

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of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action †

Influence of the Fatty Acid Metabolism on the Mode of Action of a Cisplatin(IV) Complex with Phenylbutyrate as Axial Ligands.

Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc00428e

Platinum(IV) Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] with Diclofenac Ligands in the Axial Positions: A New Class of Potent Multi-action Agents Exhibiting Selectivity to Cancer Cells.

Influence of the Number of Axial Bexarotene Ligands on the Cytotoxicity of Pt(IV) Analogs of Oxaliplatin

Synthesis, Characterization, and Cytotoxicity of the First Oxaliplatin Pt(IV) Derivative Having a TSPO Ligand in the Axial Position

Mechanisms of effects of platinum (ii) and (iv) complexes. Comparison of cisplatin and oxaliplatin with satraplatin and la-12, new pt(iv)-based drugs. (2008).

VPA does not enhance platinum binding to DNA in cisplatin-resistant neuroblastoma cancer cells

Cisplatin and valproate released from the bifunctional [Pt^(IV)Cl₂(NH₃)₂(valproato)₂] antitumor prodrug or from liposome formulations: who does what?

Pt(iv) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action

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