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Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells

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Abstract

Resistance of tumours to taxanes causes chemotherapy failure in numerous patients. Resistance is partly due to the low tumour uptake of taxanes and their rapid metabolism. Structural modifications of taxanes can reduce their P-glycoprotein-related efflux or decrease metabolism and consequently increase taxane efficiency. This study compared cytotoxicity and effects of the cell cycle, transport and metabolism of novel taxanes SB-T-1102, SB-T-1103, SB-T-1214 and SB-T-1216, fluorinated SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 and IDN5109 with paclitaxel in paclitaxel-sensitive (MDA-MB-435) and paclitaxel-resistant (NCI/ADR-RES) human cancer cells. We have shown before that NCI/ADR-RES cells were 1,000-fold less sensitive to paclitaxel than MDA-MB-435 cells in correspondence to P-glycoprotein overexpression and up to 20-fold lower uptake of the drug in the resistant cells. The uptake of novel taxanes was 1.2 to 3.8 times lower than that of paclitaxel in the MDA-MB-435 cells, but 1.5 to 6.5 times higher in NCI/ADR-RES cells. NCI/ADR-RES cells were correspondingly only 2- to 6.6-fold less sensitive than the MDA-MB-435 cells to novel taxanes. Both cell lines showed minimal metabolism of the novel taxanes which was therefore not responsible for their different sensitivity, the observed differences in their individual efficiency and higher effects than paclitaxel. All novel taxanes caused G2/M block of the cell cycle similar to paclitaxel, but lower at concentrations by order of magnitude. Thus, structural modifications of taxanes resulting in their decreased P-glycoprotein-related transport probably caused their higher efficiency than paclitaxel in multidrug-resistant NCI/ADR-RES tumour cells.

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References

  • Aoudjit F, Vuori K (2001) Integrin signalling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene 20:4995–5004

    Article  PubMed  CAS  Google Scholar 

  • Beer M, Lenaz L, Amador D (2008) Phase II study of ortataxel in taxane-resistant breast cancer. J Clin Oncol 26(20 supplement):1066, abstract

    Google Scholar 

  • Chien AJ, Moasser MM (2008) Cellular mechanisms of resistance to anthracyclines and taxanes in cancer: intrinsic and acquired. Semin Oncol 35(2 Suppl 2):S1–S14, quiz S39

    Article  PubMed  CAS  Google Scholar 

  • Choy H (2001) Taxanes in combined modality therapy for solid tumors. Review. Crit Rev Oncol Hematol 37:237–247

    Article  PubMed  CAS  Google Scholar 

  • Ehrlichová M, Václavíková R, Ojima I et al (2005) Transport and cytotoxicity of paclitaxel, docetaxel and three novel taxanes in human breast cancer cells. N-S Arch Pharmacol 372:95–105

    Article  Google Scholar 

  • Ferlini C, Distefano M, Pignatelli F, Lin S, Riva A, Bombardelli E, Mancuso S, Ojima I, Scambia G (2000) Antitumour activity of novel taxanes act at the same time as cytotoxic agents and P-glycoprotein inhibitors. Br J Cancer 83:1762–1768

    Article  PubMed  CAS  Google Scholar 

  • Freedman H, Huzil JT, Luchko T, Luduena RF, Tuzsynski JA (2009) Identification and characterization of an intermediate taxol binding site within microtubule nanopores and a mechanism for tubulin isotype binding selectivity. J Chem Inf Model 49:424–436

    Article  PubMed  CAS  Google Scholar 

  • Galletti E, Magnani M, Renzulli ML, Botta M (2007) Paclitaxel and docetaxel resistance: molecular mechanisms and development of new generation taxanes. Chem Med Chem 7:920–942

    Google Scholar 

  • Garg MB, Ackland SP (2000) Simple and sensitive high-performance liquid chromatography. Method for determination of docetaxel in human plasma and urine. J Chromatog B 748:383–388

    Article  CAS  Google Scholar 

  • Gut I, Danielova V, Holubova J, Soucek P, Kluckova H (2000) Cytotoxicity of cyclophosphamide, paclitaxel, and docetaxel for tumor cell lines in vitro: effects of concentration, time and cytochrome P450-catalyzed metabolism. Arch Toxicol 74:437–446

    Article  PubMed  CAS  Google Scholar 

  • Gut I, Václavíková R, Simek P, Ojima I, Horsky S, Soucek P, Kondrova E (2006) Metabolism of new generation taxanes in human, pig, minipig and rat liver microsomes. Xenobiotica 36:772–792

    Article  PubMed  CAS  Google Scholar 

  • Hastie TJ, Tibshirani RJ (1990) Generalized additive models. Chapman and Hall/CRC, London

    Google Scholar 

  • Kovář J, Ehrlichová M, Šmejkalová B, Zanardi I, Ojima I, Gut I (2009) Comparison of cell death-inducing effect of novel taxane SB-T-1216 and paclitaxel in breast cancer cells. Anticancer Res 29:2951–2960

    PubMed  Google Scholar 

  • Miller ML, Ojima I (2001) Chemistry and chemical biology of taxane anticancer agents. Chem Rec 1:195–211

    Article  PubMed  CAS  Google Scholar 

  • Monks A, Harris E, Hose C, Connelly J, Sausville EA (2003) Genotoxic profiling of MCF-7 breast cancer cell line elucidates gene expression modifications underlying toxicity of the anticancer drug 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole. Mol Pharmacol 63:766–772

    Article  PubMed  CAS  Google Scholar 

  • Ojima I, Slater JC, Michaud E, Kuduk SD, Bounaud PY, Vrignaud P, Bissery MC, Veith JM, Pera P, Bernacki RJ (1996) Synthesis and structure-activity relationships of the second-generation antitumor taxoids: exceptional activity against drug-resistant cancer cells. J Med Chem 39:3889–3896

    Article  PubMed  CAS  Google Scholar 

  • Rowinsky EK (1997) The development and clinical utility of taxane class of antimicrotubule chemotherapy agents. Annu Rev Med 48:353–374

    Article  PubMed  CAS  Google Scholar 

  • Sackett D, Fojo T (1997) Taxanes. Review. Canc Chemother Biol Response Modif 17:59–79

    CAS  Google Scholar 

  • Schiff PB, Horwitz SB (1981) Taxol assembles tubulin in the absence of exogenous guanosine 5′-triphosphate or microtubule-associated proteins. Biochemistry 20:3247–3252

    Article  PubMed  CAS  Google Scholar 

  • Václaviková R, Horsky S, Simek P, Gut I (2003) The paclitaxel metabolism in rat and human liver microsomes is inhibited by phenolic antioxidants. Naunyn-Schmiedebergs Arch Pharmacol 368:200–209

    Article  PubMed  Google Scholar 

  • Václaviková R, Nordgard SH, Alnaes GIG, Hubackova M, Kubala E, Kodet R, Mrhalova M, Novotny J, Gut I, Kristensen VN, Soucek P (2008) Single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1); effects on its expression and clinico-pathological characteristics in breast cancer patients. Pharmacogenetics Genom 18:263–273

    Article  Google Scholar 

  • Vobořilová J, Němcová-Fürstová V, Neubauerová J, Ojima I, Zanardi I, Gut I, Kovář J (2011) Cell death induced by novel fluorinated taxanes in drug-sensitive and drug-resistant cancer cells. Invest New Drugs 29(3):411–423

    Google Scholar 

  • Wood SN (2006) Generalized additive models: an introduction with R. Chapman and Hall/CRC, London, 391 pages

    Google Scholar 

Download references

Acknowledgments

The study was supported by the Internal Grant Agency, Czech Ministry of Health, Czech Republic [grant no.9803-3 (to I.G., R.V., M.E., P.S. ad S.H.) and grant NT 11513-5/2010 (to P.Š.)], National Cancer Institute, U. S. A. [grant CA103314 (to I.O.)] and Grant Agency of the Czech Republic [grant no. 301/09/0362 (to J.K., V.N. and J.V.)] as well as by the Institutional Research Plan of ICS AS CR No. AV0Z10300504 (to MB)

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The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Toxicogenomics Group, National Institute of Public Health, Srobarova 48, 100 42, Prague 10, Czech Republic

    Marie Ehrlichová, Jin Chen, Radka Václavíková, Stanislav Horský, Pavel Souček & Ivan Gut

  2. Biostatistics and Informatics Group, National Institute of Public Health, Srobarova 48, 100 42, Prague 10, Czech Republic

    Marek Brabec

  3. Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, 11794-3400, USA

    Iwao Ojima

  4. Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Ruská 87, 10000, Prague 10, Czech Republic

    Vlasta Němcová-Fürstová, Jana Vobořilová & Jan Kovář

  5. Laboratory of Analytical Biochemistry, Biology Centre, Academy of Sciences of the Czech Republic, Branišovská 31/1160, 370 05, České Budějovice, Czech Republic

    Petr Šimek

Authors
  1. Marie Ehrlichová
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  2. Iwao Ojima
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  3. Jin Chen
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  4. Radka Václavíková
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  5. Vlasta Němcová-Fürstová
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  6. Jana Vobořilová
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  8. Stanislav Horský
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  9. Pavel Souček
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  10. Jan Kovář
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  11. Marek Brabec
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  12. Ivan Gut
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Correspondence to Ivan Gut.

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Ehrlichová, M., Ojima, I., Chen, J. et al. Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells. Naunyn-Schmiedeberg's Arch Pharmacol 385, 1035–1048 (2012). https://doi.org/10.1007/s00210-012-0785-4

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  • DOI: https://doi.org/10.1007/s00210-012-0785-4

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