Skip to main content

Advertisement

SpringerLink
Log in

Platinum drugs and neurotoxicity: effects on intracellular calcium homeostasis

  • Original Research
  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

Abstract

[Pt(O,O′-acac)(γ-acac)(DMS)] (PtAcacDMS) is a new platinum compound showing low reactivity with nucleobases and specific reactivity with sulfur ligands intracellularly. It induces apoptosis in breast cancer cells, but appears to be less neurotoxic to the developing cerebellum than cisplatin (cisPt). The aim of this study was to assess the neurotoxicity of platinum compounds on calcium homeostasis in the dentate gyrus and Cornu Ammonis regions of the hippocampal formation during rat postnatal development. Two intracellular calcium homeostasis systems were taken for measurement, calbindin, a calcium buffer protein, and a plasma membrane calcium ATPase (PMCA1). The platinum compounds showed different effects on these markers in the two areas. One day after injection (PD11), cisPt decreased calbindin immunoreactivity and PMCA1 labeling in both regions; at PD17, the downregulation of PMCA1 persisted. Instead, PtAcacDMS produced varying effects on calbindin immunoreactivity in the two regions at PD11 and PD17; but in all cases, the changes incurred in calbindin immunoreactivity were counterbalanced by changes produced in PMCA1 expression. In conclusion, PtAcacDMS seems to affect calcium homeostasis in the central nervous system differently than cisPt. Both the platinum compounds act early to alter the calbindin buffering system. However, the most important difference between cisPt and PtAcacDMS is that, in vivo, the latter acts early to stimulate calcium efflux from nerve cells as reflected by its effect on PMCA1. The rapid onset of an activated calcium pump appears to be essential to cope with the excessive intracellular calcium concentration stemming from the downregulation of calbindin which could damage neuron function and morphology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

[Ca2+]i :

Intracellular calcium concentration

CA:

Cornu Ammonis

CB:

Calbindin

cisPt:

Cisplatin

DG:

Dentate gyrus

gl:

Granule layer

hi:

Hilus

l/ml:

Lacunosum–moleculare layer

ml:

Molecular layer

OD:

Optical density

PD:

Postnatal day

Pl:

Pyramidal layer

PMCA1:

Plasma membrane calcium ATPase1

PtAcacDMS:

[Pt(O,O′-acac)(γ-acac)(DMS)]

rl:

Radiatum layer

SD:

Standard deviation

References

  • Abraham H, Veszpremi B, Kravjak A, Kovacs K, Gomori E, Seress L. Ontogeny of calbindin immunoreactivity in the human hippocampal formation with a special emphasis on granule cells of the dentate gyrus. Int J Dev Neurosci. 2009;27:115–27.

    Article  PubMed  CAS  Google Scholar 

  • Ahmad S. Platinum–DNA interactions and subsequent cellular processes controlling sensitivity to anticancer platinum complexes. Chem Biodivers. 2010;7:543–66.

    Article  PubMed  CAS  Google Scholar 

  • Arain M, Haque M, Johal L, Mathur P, Nel W, Rais A, et al. Maturation of the adolescent brain. Neuropsychiatr Dis Treat. 2013;9:449–61.

    PubMed  Google Scholar 

  • Avella D, Pisu MB, Roda E, Gravati M, Bernocchi G. Reorganization of the rat cerebellar cortex during postnatal development following cisplatin treatment. Exp Neurol. 2006;201:131–43.

    Article  PubMed  CAS  Google Scholar 

  • Berliocchi L, Bano D, Nicotera P. Ca2+ signals and death programmes in neurons. Philos Trans R Soc Lond B Biol Sci. 2005;360:2255–8.

    Article  PubMed  CAS  Google Scholar 

  • Bernocchi G, Bottone MG, Piccolini VM, Dal Bo V, Santin G, De Pascali SA, et al. Developing central nervous system and vulnerability to platinum compounds. Chemother Res Pract. 2011. doi:10.1155/2011/315418.

    PubMed  Google Scholar 

  • Bodenner DL, Dedon PC, Keng PC, Katz JC, Borch RF. Selective protection against cis-diamminedichloroplatinum(II)-induced toxicity in kidney, gut, and bone marrow by diethyldithiocarbamate. Cancer Res. 1986;46:2751–5.

    PubMed  CAS  Google Scholar 

  • Bottone MG, Dal Bo V, Piccolini VM, Bottiroli G, De Pascali SA, Fanizzi FP, et al. Developmental expression of cellular prion protein and apoptotic molecules in the rat cerebellum: effects of platinum compounds. J Chem Neuroanat. 2012;46:19–29.

    Article  PubMed  CAS  Google Scholar 

  • Brandt MD, Jessberger S, Steiner B, Kronenberg G, Reuter K, Bick-Sander A, et al. Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice. Mol Cell Neurosci. 2003;24:603–13.

    Article  PubMed  CAS  Google Scholar 

  • Braun K. Calcium-binding proteins in avian and mammalian central nervous system: localization, development and possible functions. Prog Histochem Cytochem. 1990;21:1–64.

    Article  PubMed  CAS  Google Scholar 

  • Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol. 2000;18:2695–701.

    PubMed  CAS  Google Scholar 

  • Carafoli E, Brini M. Calcium pumps: structural basis for and mechanism of calcium transmembrane transport. Curr Opin Chem Biol. 2000;4:152–61.

    Article  PubMed  CAS  Google Scholar 

  • Cavaletti G, Marzorati L, Bogliun G, Colombo N, Marzola M, Pittelli MR, et al. Cisplatin-induced peripheral neurotoxicity is dependent on total-dose intensity and single-dose intensity. Cancer. 1992;69:203–7.

    Article  PubMed  CAS  Google Scholar 

  • Cerri S, Piccolini VM, Santin G, Bottone MG, De Pascali SA, Migoni D, et al. The developmental neurotoxicity study of platinum compounds. Effects of cisplatin versus a novel Pt(II) complex on rat cerebellum. Neurotoxicol Teratol. 2011;33:273–81.

    Article  PubMed  CAS  Google Scholar 

  • Chandra S. Quantitative imaging of chemical composition in single cells by secondary Ion mass spectrometry: cisplatin affects calcium stores in renal epithelial cells. Methods Mol Biol. 2010;656:113–30.

    Article  PubMed  CAS  Google Scholar 

  • Danglot L, Triller A, Marty S. The development of hippocampal interneurons in rodents. Hippocampus. 2006;16:1032–60.

    Article  PubMed  CAS  Google Scholar 

  • De Pascali SA, Papadia P, Ciccarese A, Pacifico C, Fanizzi FP. First examples of βdiketonate platinum II complexes with sulfoxide ligands. Eur J Inorg Chem. 2005;5:788–96.

    Article  Google Scholar 

  • De Pascali SA, Papadia P, Capoccia S, Marchiò L, Lanfranchi M, Ciccarese A, et al. Hard/soft selectivity in ligand substitution reactions of β-diketonate platinum(II) complexes. Dalton Trans. 2009;37:7786–95.

    Article  PubMed  Google Scholar 

  • Dietrich J, Han R, Yang Y, Mayer-Pröschel M, Noble M. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol. 2006;5:22.

    Article  PubMed  Google Scholar 

  • Florea AM, Büsselberg D. Occurrence, use and potential toxic effects of metals and metal compounds. Biometals. 2006;19:419–27.

    Article  PubMed  CAS  Google Scholar 

  • Florea AM, Büsselberg D. Anti-cancer drugs interfere with intracellular calcium signaling. Neurotoxicology. 2009;30:803–10.

    Article  PubMed  CAS  Google Scholar 

  • Freund TF, Buszaki G. Interneurons of the hippocampus. Hippocampus. 1996;6:347–470.

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez VM, Fuertes MA, Alonso C, Perez JM. Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol. 2001;59:657–63.

    PubMed  CAS  Google Scholar 

  • Jaggi AS, Singh N. Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy. Toxicology. 2012;291:1–9.

    Article  PubMed  CAS  Google Scholar 

  • Kawai Y, Nakao T, Kunimura N, Kohda Y, Gemba M. Relationship of intracellular calcium and oxygen radicals to cisplatin-related renal cell injury. J Pharmacol Sci. 2006;100:65–72.

    Article  PubMed  CAS  Google Scholar 

  • Kenyon KA, Bushong EA, Mauer AS, Strehler EE, Weinberg RJ, Burette AC. Cellular and subcellular localization of the neuron-specific plasma membrane calcium ATPase PMCA1a in the rat brain. J Comp Neurol. 2010;518:3169–83.

    Article  PubMed  CAS  Google Scholar 

  • Kip SN, Gray NW, Burette A, Canbay A, Weinberg RJ, Strehler EE. Changes in the expression of plasma membrane calcium extrusion systems during the maturation of hippocampal neurons. Hippocampus. 2006;16:20–34.

    Article  PubMed  CAS  Google Scholar 

  • Liang X, Huang Y. Intracellular free calcium concentration and cisplatin resistance in human lung adenocarcinoma A549 cells. Biosci Rep. 2000;20:129–38.

    Article  PubMed  CAS  Google Scholar 

  • Lohmann C. Calcium signaling and the development of specific neuronal connections. Prog Brain Res. 2009;75:443–52.

    Article  Google Scholar 

  • Magloczky Z, Freund TF. Selective neuronal death in the contralateral hippocampus following unilateral kainate injections into the CA3 subfield. Neuroscience. 1993;56:317–35.

    Article  PubMed  CAS  Google Scholar 

  • Marcos D, Sepulveda MR, Berrocal M, Mata AM. Ontogeny of ATP hydrolysis and isoform expression of the plasma membrane Ca(2+)-ATPase in mouse brain. BMC Neurosci. 2009;10:112.

    Article  PubMed  Google Scholar 

  • Maskeya D, Pradhanb J, Aryalc B, Leed CM, Choia IY, Parka KS, et al. Chronic 835-MHz radiofrequency exposure to mice hippocampus alters the distribution of calbindin and GFAP immunoreactivity. Brain Res. 2010;1346:237–46.

    Article  Google Scholar 

  • Mata AM, Sepulveda MR. Calcium pumps in the central nervous system. Brain Res Brain Res Rev. 2005;49:398–405.

    Article  PubMed  CAS  Google Scholar 

  • Mata AM, Sepulveda MR. Plasma membrane Ca-ATPases in the nervous system during development and ageing. World J Biol Chem. 2010;1:229–34.

    Article  PubMed  Google Scholar 

  • Mattson MP. Calcium and neurodegeneration. Aging Cell. 2007;6:337–50.

    Article  PubMed  CAS  Google Scholar 

  • Meijer C, de Vries EG, Marmiroli P, Tredici G, Frattola L, Cavaletti G. Cisplatin-induced DNA-platination in experimental dorsal root ganglia neuronopathy. Neurotoxicology. 1999;20:883–7.

    PubMed  CAS  Google Scholar 

  • Monje M, Dietrich J. Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis. Behav Brain Res. 2012;227:376–9.

    Article  PubMed  Google Scholar 

  • Muscella A, Calabriso N, De Pascali SA, Urso L, Ciccarese A, Fanizzi FP, et al. New platinum(II) complexes containing both an O,O′-chelated acetylacetonate ligand and a sulfur ligand in the platinum coordination sphere induce apoptosis in HeLa cervical carcinoma cells. Biochem Pharmacol. 2007;74:28–40.

    Article  PubMed  CAS  Google Scholar 

  • Muscella A, Calabriso N, Fanizzi FP, De Pascali SA, Urso L, Ciccarese A, et al. [Pt(O,O′-acac)(γ-acac)(DMS)], a new Pt compound exerting fast cytotoxicity in MCF-7 breast cancer cells via the mitochondrial apoptotic pathway. Brit J Pharmacol. 2008;153:34–49.

    Article  CAS  Google Scholar 

  • Muscella A, Calabriso N, Vetrugno C, Urso L, Fanizzi FP, De Pascali SA, et al. Sublethal concentrations of the platinum(II) complex [Pt(O,O-acac)(gammaacac)(DMS)] alter the motility and induce anoikis in MCF-7 cells. Br J Pharmacol. 2010;160:1362–77.

    Article  PubMed  CAS  Google Scholar 

  • Muscella A, Calabrisio N, Vetrugno C, Fanizzi FP, De Pascali SA, Storelli C, et al. The platinum (II) complex [Pt(O,O′-acac)(gamma-acac)(DMS)] alters the intracellular calcium homeostasis in MCF-7 breast cancer cells. Biochem Pharmacol. 2011;81:91–103.

    Article  PubMed  CAS  Google Scholar 

  • Nagerl UV, Mody I, Jeub M, Lie AA, Elger CE, Beck H. Surviving granule cells of the sclerotic human hippocampus have reduced Ca(2+) influx because of a loss of calbindin-D(28k) in temporal lobe epilepsy. J Neurosci. 2000;20:1831–6.

    PubMed  CAS  Google Scholar 

  • Pisu MB, Roda E, Guioli S, Avella D, Bottone MG, Bernocchi G. Proliferation and migration of granule cells in the developing rat cerebellum: cisplatin effects. Anat Rec A Discov Mol Cell Evol Biol. 2005;287:1226–35.

    Article  PubMed  Google Scholar 

  • Prestayko AW, D'Aoust JC, Issell BF, Crooke ST. Cisplatin (cis-diamminedichloroplatinum II). Cancer Treat Rev. 1979;6:17–35.

    Article  PubMed  CAS  Google Scholar 

  • Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 2007;33:9–23.

    Article  PubMed  CAS  Google Scholar 

  • Sancho-Martínez SM, Prieto-García L, Prieto M, López-Novoa JM, López-Hernández FJ. Subcellular targets of cisplatin cytotoxicity: an integrated view. Pharmacol Ther. 2012;136:35–55.

    Article  PubMed  Google Scholar 

  • Seigers R, Fardell JE. Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev. 2011;35:729–41.

    Article  PubMed  Google Scholar 

  • Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22:7265–79.

    Article  PubMed  CAS  Google Scholar 

  • Sioka C, Kyritsis A. Central and peripheral nervous system toxicity of common chemotherapeutic agents. Cancer Chemother Pharmacol. 2009;63:761–7.

    Article  PubMed  CAS  Google Scholar 

  • Splettstoesser F, Florea AM, Büsselberg D. IP(3) receptor antagonist, 2-APB, attenuates cisplatin induced Ca2+-influx in HeLa-S3 cells and prevents activation of calpain and induction of apoptosis. Br J Pharmacol. 2007;151:1176–86.

    Article  PubMed  CAS  Google Scholar 

  • Strehler EE, Zacharias DA. Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps. Physiol Rev. 2001;81:21–50.

    PubMed  CAS  Google Scholar 

  • Sugimoto S, Yamamoto YL, Nagahiro S, Diksic M. Permeability change and brain tissue damage after intracarotid administration of cisplatin studied by double-tracer autoradiography in rats. J Neurooncol. 1995;24:229–40.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from “Fondi di Ateneo per la Ricerca” (FAR, University of Pavia), “Fondazione Banca del Monte di Lombardia” (Italy) and “Programmi di Ricerca di Rilevante Interesse Nazionale” (PRIN, 2009ZFPSPW).

Author information

Authors and Affiliations

  1. Dipartimento di Biologia e Biotecnologie “L. Spallanzani” Università di Pavia, via Ferrata 9, 27100, Pavia, Italy

    Valeria Maria Piccolini, Maria Grazia Bottone & Graziella Bernocchi

  2. Sezione di Istochimica e Citometria, Istituto di Genetica Molecolare del CNR, via Ferrata 9, 27100, Pavia, Italy

    Maria Grazia Bottone & Giovanni Bottiroli

  3. Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, 73100, Lecce, Italy

    Sandra Angelica De Pascali & Francesco Paolo Fanizzi

Authors
  1. Valeria Maria Piccolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Grazia Bottone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giovanni Bottiroli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandra Angelica De Pascali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco Paolo Fanizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Graziella Bernocchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Graziella Bernocchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Piccolini, V.M., Bottone, M.G., Bottiroli, G. et al. Platinum drugs and neurotoxicity: effects on intracellular calcium homeostasis. Cell Biol Toxicol 29, 339–353 (2013). https://doi.org/10.1007/s10565-013-9252-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-013-9252-3

Keywords

Search

Navigation