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Impact of intracellular chloride concentration on cisplatin accumulation in sensitive and resistant GLC4 cells

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Abstract

Resistance to cisplatin [cis-diamminedichloroplatinum(II), CDDP] chemotherapy is a major problem in the clinic. Understanding the molecular basis of the intracellular accumulation of CDDP and other platinum-based anticancer drugs is of importance in delineating the mechanism of resistance to these clinically important therapies. Different molecular mechanisms may coexist, but defective uptake of CDDP is one of the most consistently identified characteristics of cells selected for CDDP resistance. We have studied the impact of intracellular chloride concentration on platinum-based compound accumulation in the human GLC4, GLC4/CDDP, and K562 tumor cell lines. We show that (1) a decrease of intracellular chloride concentration yielded an increase of CDDP accumulation and vice versa and (2) the intracellular chloride concentration in GLC4/CDDP cells is higher than in sensitive cells, whereas CDDP accumulation shows the opposite behavior. The identification of chloride as a critical determinant of CDDP intracellular accumulation and the molecular mechanisms by which CDDP-resistant cells modulate chloride concentration may allow alternative therapeutic approaches. Our findings indicate that increase of intracellular chloride concentration may be a major determinant of CDDP resistance.

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Acknowledgments

This research was supported by grants from Université Paris 13 and CNRS. We thank to Ricarda Riina for her help.

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Authors and Affiliations

  1. Laboratoire de Biophysique Moléculaire Cellulaire et Tissulaire (BioMoCeTi), UMR-CNRS 7033, UMPC Université Paris 6 and Université Paris 13, UFR SMBH, Université Paris 13, 74 rue Marcel Cachin, 93017, Bobigny, France

    Milena Salerno, Dalila Yahia, Simplice Dzamitika & Arlette Garnier-Suillerot

  2. Department of Medical Oncology, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands

    Elisabeth de Vries

  3. Departamento de Quimica, ICEx, Universidade Federal de Minas Gerais, Avenida Antonio Carlos, 6627, Belo Horizonte, MG, 31270-901, Brazil

    Elene Pereira-Maia

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  1. Milena Salerno
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  2. Dalila Yahia
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  3. Simplice Dzamitika
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  4. Elisabeth de Vries
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  5. Elene Pereira-Maia
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Correspondence to Milena Salerno.

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Salerno, M., Yahia, D., Dzamitika, S. et al. Impact of intracellular chloride concentration on cisplatin accumulation in sensitive and resistant GLC4 cells. J Biol Inorg Chem 14, 123–132 (2009). https://doi.org/10.1007/s00775-008-0430-3

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  • DOI: https://doi.org/10.1007/s00775-008-0430-3

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