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

Content Provider	Europe PMC
Author	Mendrina, Theresa Poetsch, Isabella Schueffl, Hemma Baier, Dina Pirker, Christine Ries, Alexander Keppler, Bernhard K. Kowol, Christian R. Gibson, Dan Grusch, Michael Berger, Walter Heffeter, Petra
Editor	Valente, Andreia Marques Tomaz, Ana Isabel
Copyright Year	2023
Abstract	For a variety of cancer types, platinum compounds are still among the best treatment options. However, their application is limited by side effects and drug resistance. Consequently, multi-targeted platinum(IV) prodrugs that target specific traits of the malignant tissue are interesting new candidates. Recently, cisPt(PhB)2 was synthesized which, upon reduction in the malignant tissue, releases phenylbutyrate (PhB), a metabolically active fatty acid analog, in addition to cisplatin. In this study, we in-depth investigated the anticancer properties of this new complex in cell culture and in mouse allograft experiments. CisPt(PhB)2 showed a distinctly improved anticancer activity compared to cisplatin as well as to PhB alone and was able to overcome various frequently occurring drug resistance mechanisms. Furthermore, we observed that differences in the cellular fatty acid metabolism and mitochondrial activity distinctly impacted the drug’s mode of action. Subsequent analyses revealed that “Warburg-like” cells, which are characterized by deficient mitochondrial function and fatty acid catabolism, are less capable of coping with cisPt(PhB)2 leading to rapid induction of a non-apoptotic form of cell death. Summarizing, cisPt(PhB)2 is a new orally applicable platinum(IV) prodrug with promising activity especially against cisplatin-resistant cancer cells with “Warburg-like” properties.
Journal	Pharmaceutics
Volume Number	15
PubMed Central reference number	PMC9967619
Issue Number	2
PubMed reference number	36839999
e-ISSN	19994923
DOI	10.3390/pharmaceutics15020677
Language	English
Publisher	MDPI
Publisher Date	2023-02-16
Access Restriction	Open
Rights License	Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). © 2023 by the authors.
Subject Keyword	platinum(IV) phenylbutyrate cisplatin prodrug lipid metabolism Warburg effect
Content Type	Text
Resource Type	Article
Subject	Pharmaceutical Science