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Pharmaceutics
Volume 15
Issue 2
10.3390/pharmaceutics15020677
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Article

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

by
Theresa Mendrina
1,2,3,†,
Isabella Poetsch
1,2,3,†,
Hemma Schueffl
1,3,
Dina Baier
1,2,3,
Christine Pirker
1,
Alexander Ries
1,
Bernhard K. Keppler
2,3,
Christian R. Kowol
2,3,
Dan Gibson
4,
Michael Grusch
1,
Walter Berger
1,3 and
Petra Heffeter
1,3,*
1
Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
2
Faculty of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria
3
Research Cluster “Translational Cancer Therapy Research”, 1090 Vienna, Austria
4
Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem 91120, Israel
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceutics 2023, 15(2), 677; https://doi.org/10.3390/pharmaceutics15020677
Submission received: 28 January 2023 / Revised: 8 February 2023 / Accepted: 11 February 2023 / Published: 16 February 2023
(This article belongs to the Special Issue Metallodrugs in Cancer Therapy: The Newest Candidates in the Field)
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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.
Keywords: platinum(IV); phenylbutyrate; cisplatin; prodrug; lipid metabolism; Warburg effect platinum(IV); phenylbutyrate; cisplatin; prodrug; lipid metabolism; Warburg effect

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MDPI and ACS Style

Mendrina, T.; Poetsch, I.; Schueffl, H.; Baier, D.; Pirker, C.; Ries, A.; Keppler, B.K.; Kowol, C.R.; Gibson, D.; Grusch, M.; et al. Influence of the Fatty Acid Metabolism on the Mode of Action of a Cisplatin(IV) Complex with Phenylbutyrate as Axial Ligands. Pharmaceutics 2023, 15, 677. https://doi.org/10.3390/pharmaceutics15020677

AMA Style

Mendrina T, Poetsch I, Schueffl H, Baier D, Pirker C, Ries A, Keppler BK, Kowol CR, Gibson D, Grusch M, et al. Influence of the Fatty Acid Metabolism on the Mode of Action of a Cisplatin(IV) Complex with Phenylbutyrate as Axial Ligands. Pharmaceutics. 2023; 15(2):677. https://doi.org/10.3390/pharmaceutics15020677

Chicago/Turabian Style

Mendrina, Theresa, Isabella Poetsch, Hemma Schueffl, Dina Baier, Christine Pirker, Alexander Ries, Bernhard K. Keppler, Christian R. Kowol, Dan Gibson, Michael Grusch, and et al. 2023. "Influence of the Fatty Acid Metabolism on the Mode of Action of a Cisplatin(IV) Complex with Phenylbutyrate as Axial Ligands" Pharmaceutics 15, no. 2: 677. https://doi.org/10.3390/pharmaceutics15020677

APA Style

Mendrina, T., Poetsch, I., Schueffl, H., Baier, D., Pirker, C., Ries, A., Keppler, B. K., Kowol, C. R., Gibson, D., Grusch, M., Berger, W., & Heffeter, P. (2023). Influence of the Fatty Acid Metabolism on the Mode of Action of a Cisplatin(IV) Complex with Phenylbutyrate as Axial Ligands. Pharmaceutics, 15(2), 677. https://doi.org/10.3390/pharmaceutics15020677

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