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In vitro nephrotoxicity studies of established and experimental platinum-based compounds

Schoch, Sarah LU ; Sen, Vasily ; Brenner, Walburgis ; Hartwig, Andrea and Köberle, Beate (2021) In Biomedicines 9(8).
Abstract

Cisplatin is one of the most commonly used drugs for the treatment of various solid cancers. However, its efficacy is restricted by severe side effects, especially dose-limiting nephrotoxicity. New platinum-based compounds are designed to overcome this limitation. Previous investigations showed that the platinum(IV)–nitroxyl complex PN149 is highly cytotoxic in various tumor cell lines. In the present study, investigations with PN149 were extended to normal human kidney tubule epithelia. Coincident with higher intracellular platinum accumulation, the cytotoxicity of PN149 in the proximal tubule epithelial cell line ciPTEC was more pronounced compared to the established platinum chemotherapeutics cisplatin, carboplatin and oxaliplatin.... (More)

Cisplatin is one of the most commonly used drugs for the treatment of various solid cancers. However, its efficacy is restricted by severe side effects, especially dose-limiting nephrotoxicity. New platinum-based compounds are designed to overcome this limitation. Previous investigations showed that the platinum(IV)–nitroxyl complex PN149 is highly cytotoxic in various tumor cell lines. In the present study, investigations with PN149 were extended to normal human kidney tubule epithelia. Coincident with higher intracellular platinum accumulation, the cytotoxicity of PN149 in the proximal tubule epithelial cell line ciPTEC was more pronounced compared to the established platinum chemotherapeutics cisplatin, carboplatin and oxaliplatin. Quantitative gene expression profiling revealed the induction of ROS-inducible and anti-oxidative genes, suggesting an oxidative stress response by PN149. However, in contrast to cisplatin, no pro-inflammatory response was observed. Genes coding for distinct DNA damage response factors and genes related to apoptosis were up-regulated, indicating the activation of the DNA damage response system and induction of the apoptotic cascade by PN149. Altogether, a comparable transcriptional response was observed for PN149 and the platinum chemotherapeutics. However, the lack of inflammatory activity, which is a possible cause contributing to toxicity in human renal proximal tubule epithelia, might indicate the reduced nephrotoxic potential of PN149.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Chemotherapeutic drugs, Cisplatin, DNA damage response, Gene expression profiling, Nephrotoxicity, Platinum drugs
in
Biomedicines
volume
9
issue
8
article number
1033
publisher
MDPI AG
external identifiers
  • scopus:85113375375
  • pmid:34440237
ISSN
2227-9059
DOI
10.3390/biomedicines9081033
language
English
LU publication?
yes
id
8393996e-43c3-405a-82eb-ddee9a6499bc
date added to LUP
2021-09-20 15:52:46
date last changed
2024-06-15 16:36:00
@article{8393996e-43c3-405a-82eb-ddee9a6499bc,
  abstract     = {{<p>Cisplatin is one of the most commonly used drugs for the treatment of various solid cancers. However, its efficacy is restricted by severe side effects, especially dose-limiting nephrotoxicity. New platinum-based compounds are designed to overcome this limitation. Previous investigations showed that the platinum(IV)–nitroxyl complex PN149 is highly cytotoxic in various tumor cell lines. In the present study, investigations with PN149 were extended to normal human kidney tubule epithelia. Coincident with higher intracellular platinum accumulation, the cytotoxicity of PN149 in the proximal tubule epithelial cell line ciPTEC was more pronounced compared to the established platinum chemotherapeutics cisplatin, carboplatin and oxaliplatin. Quantitative gene expression profiling revealed the induction of ROS-inducible and anti-oxidative genes, suggesting an oxidative stress response by PN149. However, in contrast to cisplatin, no pro-inflammatory response was observed. Genes coding for distinct DNA damage response factors and genes related to apoptosis were up-regulated, indicating the activation of the DNA damage response system and induction of the apoptotic cascade by PN149. Altogether, a comparable transcriptional response was observed for PN149 and the platinum chemotherapeutics. However, the lack of inflammatory activity, which is a possible cause contributing to toxicity in human renal proximal tubule epithelia, might indicate the reduced nephrotoxic potential of PN149.</p>}},
  author       = {{Schoch, Sarah and Sen, Vasily and Brenner, Walburgis and Hartwig, Andrea and Köberle, Beate}},
  issn         = {{2227-9059}},
  keywords     = {{Chemotherapeutic drugs; Cisplatin; DNA damage response; Gene expression profiling; Nephrotoxicity; Platinum drugs}},
  language     = {{eng}},
  number       = {{8}},
  publisher    = {{MDPI AG}},
  series       = {{Biomedicines}},
  title        = {{In vitro nephrotoxicity studies of established and experimental platinum-based compounds}},
  url          = {{http://dx.doi.org/10.3390/biomedicines9081033}},
  doi          = {{10.3390/biomedicines9081033}},
  volume       = {{9}},
  year         = {{2021}},
}