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The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin
BACKGROUND: Cisplatin and its derivatives are commonly used anti-cancer drugs. However, cisplatin has clinical limitations including serious side effects and frequent emergence of intrinsic or acquired resistance. Thus, the novel platinum(IV) complex LA-12 represents a promising treatment modality,...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893458/ https://www.ncbi.nlm.nih.gov/pubmed/20550649 http://dx.doi.org/10.1186/1476-4598-9-147 |
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author | Kvardova, Veronika Hrstka, Roman Walerych, Dawid Muller, Petr Matoulkova, Eva Hruskova, Veronika Stelclova, Dagmar Sova, Petr Vojtesek, Borivoj |
author_facet | Kvardova, Veronika Hrstka, Roman Walerych, Dawid Muller, Petr Matoulkova, Eva Hruskova, Veronika Stelclova, Dagmar Sova, Petr Vojtesek, Borivoj |
author_sort | Kvardova, Veronika |
collection | PubMed |
description | BACKGROUND: Cisplatin and its derivatives are commonly used anti-cancer drugs. However, cisplatin has clinical limitations including serious side effects and frequent emergence of intrinsic or acquired resistance. Thus, the novel platinum(IV) complex LA-12 represents a promising treatment modality, which shows increased intracellular penetration resulting in improved cytotoxicity in various cancer cell lines, including cisplatin resistant cells. RESULTS: LA-12 disrupts cellular proliferation regardless of the p53 status in the cells, however the potency of the drug is greatly enhanced by the presence of a functional p53, indicating several mechanisms of action. Similarly to cisplatin, an interaction of LA-12 with molecular chaperone Hsp90 was proposed. Binding of LA-12 to Hsp90 was demonstrated by Hsp90 immunoprecipitation followed by platinum measurement using atomic absorption spectrometry (AAS). An inhibitory effect of LA-12 on Hsp90 chaperoning function was shown by decrease of Hsp90-assisted wild-type p53 binding to p21(WAF1 )promoter sequence in vitro and by accelerated ubiqutination and degradation of primarily unfolded mutant p53 proteins in cells exposed to LA-12. CONCLUSIONS: To generalize our findings, LA-12 induced degradation of other Hsp90 client proteins such as Cyclin D1 and estrogen receptor was shown and proved as more efficient in comparison with cisplatin. This newly characterised molecular mechanism of action opens opportunities to design new cancer treatment strategy profitable from unique LA-12 properties, which combine DNA damaging and Hsp90 inhibitory effects. |
format | Text |
id | pubmed-2893458 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-28934582010-06-30 The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin Kvardova, Veronika Hrstka, Roman Walerych, Dawid Muller, Petr Matoulkova, Eva Hruskova, Veronika Stelclova, Dagmar Sova, Petr Vojtesek, Borivoj Mol Cancer Research BACKGROUND: Cisplatin and its derivatives are commonly used anti-cancer drugs. However, cisplatin has clinical limitations including serious side effects and frequent emergence of intrinsic or acquired resistance. Thus, the novel platinum(IV) complex LA-12 represents a promising treatment modality, which shows increased intracellular penetration resulting in improved cytotoxicity in various cancer cell lines, including cisplatin resistant cells. RESULTS: LA-12 disrupts cellular proliferation regardless of the p53 status in the cells, however the potency of the drug is greatly enhanced by the presence of a functional p53, indicating several mechanisms of action. Similarly to cisplatin, an interaction of LA-12 with molecular chaperone Hsp90 was proposed. Binding of LA-12 to Hsp90 was demonstrated by Hsp90 immunoprecipitation followed by platinum measurement using atomic absorption spectrometry (AAS). An inhibitory effect of LA-12 on Hsp90 chaperoning function was shown by decrease of Hsp90-assisted wild-type p53 binding to p21(WAF1 )promoter sequence in vitro and by accelerated ubiqutination and degradation of primarily unfolded mutant p53 proteins in cells exposed to LA-12. CONCLUSIONS: To generalize our findings, LA-12 induced degradation of other Hsp90 client proteins such as Cyclin D1 and estrogen receptor was shown and proved as more efficient in comparison with cisplatin. This newly characterised molecular mechanism of action opens opportunities to design new cancer treatment strategy profitable from unique LA-12 properties, which combine DNA damaging and Hsp90 inhibitory effects. BioMed Central 2010-06-15 /pmc/articles/PMC2893458/ /pubmed/20550649 http://dx.doi.org/10.1186/1476-4598-9-147 Text en Copyright ©2010 Kvardova et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Kvardova, Veronika Hrstka, Roman Walerych, Dawid Muller, Petr Matoulkova, Eva Hruskova, Veronika Stelclova, Dagmar Sova, Petr Vojtesek, Borivoj The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin |
title | The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin |
title_full | The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin |
title_fullStr | The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin |
title_full_unstemmed | The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin |
title_short | The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin |
title_sort | new platinum(iv) derivative la-12 shows stronger inhibitory effect on hsp90 function compared to cisplatin |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893458/ https://www.ncbi.nlm.nih.gov/pubmed/20550649 http://dx.doi.org/10.1186/1476-4598-9-147 |
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