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The effect of cellular environment and p53 status on the mode of action of the platinum derivative LA-12

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Summary

In this study, we characterized the effects of LA-12 on tumor cell lines possessing wild type p53 and on p53-deficient/mutant cell lines and the results were compared to those obtained using cisplatin. We have determined changes of p53 levels, of its transcriptional activity, of its posttranscriptional modifications and the effect of the treatment on the cell cycle, on the induction of apoptosis and on gene expression. LA-12 induces weak accumulation of both transcriptionally active p53 tumor suppressor and of p21WAF1/CIP1 protein. LA-12 and cisplatin also significantly differ in their effects on apoptosis and cell cycle and on gene expression spectra in studied cell lines. LA-12 induces higher apoptosis levels in comparison with those induced by cisplatin, especially in p53-deficient H1299 cells and in MCF-7DD cells with transcriptionally inactive p53. We suggest that LA-12-mediated apoptosis is not fully dependent on p53. This confirms the therapeutic potential of LA-12 as a more potent cytostatic agent for both tumor cells expressing wild type p53 and for p53-deficient or mutant cells.

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Acknowledgments

This work was supported by PLIVA-Lachema a. s. and IGA MZ CR NS/9812-4.

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Authors and Affiliations

  1. Department of Oncological and Experimental Pathology, Masaryk Memorial Cancer Institute, Žlutý kopec 7, 656 53, Brno, Czech Republic

    Eva Roubalová, Veronika Kvardová, Roman Hrstka, Šárka Bořilová, Eva Michalová, Petr Müller & Bořivoj Vojtěšek

  2. Research and Development, PLIVA-Lachema a.s., Karásek 1, 621 33, Brno, Czech Republic

    Petr Sova

  3. Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Žlutý kopec 7, 656 53, Brno, Czech Republic

    Lenka Dubská

  4. Department of Biology and Wildlife Diseases, Faculty of Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42, Brno, Czech Republic

    Eva Roubalová

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  1. Eva Roubalová
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Correspondence to Bořivoj Vojtěšek.

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Eva Roubalová and Veronika Kvardová contributed equally to this work.

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Roubalová, E., Kvardová, V., Hrstka, R. et al. The effect of cellular environment and p53 status on the mode of action of the platinum derivative LA-12. Invest New Drugs 28, 445–453 (2010). https://doi.org/10.1007/s10637-009-9270-4

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