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Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics

Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cis...

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Autores principales: Schoch, Sarah, Gajewski, Sabine, Rothfuß, Jana, Hartwig, Andrea, Köberle, Beate
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555145/
https://www.ncbi.nlm.nih.gov/pubmed/32967255
http://dx.doi.org/10.3390/ijms21186928
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author Schoch, Sarah
Gajewski, Sabine
Rothfuß, Jana
Hartwig, Andrea
Köberle, Beate
author_facet Schoch, Sarah
Gajewski, Sabine
Rothfuß, Jana
Hartwig, Andrea
Köberle, Beate
author_sort Schoch, Sarah
collection PubMed
description Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cisplatin and oxaliplatin compared to carboplatin, with induction of apoptosis as the preferred mode of cell death. Gene expression profiling displayed modulation of genes related to DNA damage response/repair, cell cycle regulation and apoptosis which was more pronounced upon oxaliplatin treatment. Furthermore, repression of specific DNA repair genes was restricted to oxaliplatin. Transcriptional level observations were further analyzed on the functional level. Uptake studies revealed low intracellular platinum accumulation and DNA platination upon carboplatin treatment. Removal of overall DNA platination was comparable for the three drugs. However, no processing of oxaliplatin-induced interstrand crosslinks was observed. Cisplatin and carboplatin influenced cell cycle distribution comparably, while oxaliplatin had no effect. Altogether, we found a similar mode of action for cisplatin and carboplatin, while the activity of oxaliplatin appeared to differ. This might be clinically relevant as due to the difference in mode of action oxaliplatin could be active in tumors which show resistance towards cisplatin and carboplatin.
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spelling pubmed-75551452020-10-14 Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics Schoch, Sarah Gajewski, Sabine Rothfuß, Jana Hartwig, Andrea Köberle, Beate Int J Mol Sci Article Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cisplatin and oxaliplatin compared to carboplatin, with induction of apoptosis as the preferred mode of cell death. Gene expression profiling displayed modulation of genes related to DNA damage response/repair, cell cycle regulation and apoptosis which was more pronounced upon oxaliplatin treatment. Furthermore, repression of specific DNA repair genes was restricted to oxaliplatin. Transcriptional level observations were further analyzed on the functional level. Uptake studies revealed low intracellular platinum accumulation and DNA platination upon carboplatin treatment. Removal of overall DNA platination was comparable for the three drugs. However, no processing of oxaliplatin-induced interstrand crosslinks was observed. Cisplatin and carboplatin influenced cell cycle distribution comparably, while oxaliplatin had no effect. Altogether, we found a similar mode of action for cisplatin and carboplatin, while the activity of oxaliplatin appeared to differ. This might be clinically relevant as due to the difference in mode of action oxaliplatin could be active in tumors which show resistance towards cisplatin and carboplatin. MDPI 2020-09-21 /pmc/articles/PMC7555145/ /pubmed/32967255 http://dx.doi.org/10.3390/ijms21186928 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Schoch, Sarah
Gajewski, Sabine
Rothfuß, Jana
Hartwig, Andrea
Köberle, Beate
Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics
title Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics
title_full Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics
title_fullStr Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics
title_full_unstemmed Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics
title_short Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics
title_sort comparative study of the mode of action of clinically approved platinum-based chemotherapeutics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555145/
https://www.ncbi.nlm.nih.gov/pubmed/32967255
http://dx.doi.org/10.3390/ijms21186928
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