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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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SYSNO ASEP 0471983 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Pt(IV) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action Author(s) Raveendran, R. (IL)
Braude, J.P. (IT)
Wexselblatt, E. (IL)
Novohradský, Vojtěch (BFU-R) ORCID
Stuchlikova, O. (CZ)
Brabec, Viktor (BFU-R) RID, ORCID
Gandin, V. (IT)
Gibson, D. (IL)Number of authors 8 Source Title Chemical Science . - : Royal Society of Chemistry - ISSN 2041-6520
Roč. 7, č. 3 (2016), s. 2381-2391Number of pages 11 s. Publication form Print - P Language eng - English Country GB - United Kingdom Keywords histone deacetylase inhibitors ; cell lung-cancer ; in-vitro cytotoxicity Subject RIV BO - Biophysics R&D Projects GA14-21053S GA ČR - Czech Science Foundation (CSF) Institutional support BFU-R - RVO:68081707 UT WOS 000371021900096 DOI https://doi.org/10.1039/c5sc04205d Annotation Our study demonstrates that Pt(IV) derivative of cisplatin, with two axial PhB ligands, ctc-[Pt(NH3)(2)(PhB)(2)Cl-2], 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)(2)Cl-2] 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)(2)Cl-2] 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)(2)Cl-2] 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)(2)Cl-2] is significantly more potent than its valproate analog ctc-[Pt(NH3)(2)(VPA)(2)Cl-2]. 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. Workplace Institute of Biophysics Contact Jana Poláková, polakova@ibp.cz, Tel.: 541 517 244 Year of Publishing 2017
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