Comparative study of the mode of action of clinically approved platinum-based chemotherapeutics

Sarah Schoch, Sabine Gajewski, Jana Rothfuß, Andrea Hartwig, Beate Köberle

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number6928
Number of pages20
JournalInternational Journal of Molecular Sciences
Volume21
Issue number18
DOIs
Publication statusPublished - 2020

Subject classification (UKÄ)

  • Cancer and Oncology

Free keywords

  • Cisplatin analogues
  • DNA damage response
  • Gene expression profiling
  • Tumor cells

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