Skip to main content
SpringerLink
Log in

Targeting Multidrug Resistance in Neuroblastoma

  • Chapter
  • First Online:
Neuroblastoma

Part of the book series: Pediatric Cancer ((PECA,volume 1))

Abstract

The majority of children with high-risk neuroblastoma eventually relapse with disease refractory to treatment. Conventional chemotherapeutic approaches to high-risk neuroblastoma are at or approaching their tolerance limits, implying that future improvements in outcome for these patients are likely to come from more targeted therapies, including those that either bypass or reverse multidrug resistance. To achieve this aim, additional insights into drug resistance mechanisms are essential. Significant advances in our understanding of multidrug resistance in neuroblastoma have recently come through a combination of comprehensive patient sample studies, realistic mouse genetic models, and the development of small molecule inhibitors targeting resistance mechanisms. These combined approaches are outlined here for the drug efflux pump MRP1 and for the p14ARF-MDM2-p53 pathway.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Barbieri E, Mehta P, Chen Z, Zhang L, Slack A, Berg S, Shohet JM (2006) MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death. Mol Cancer Ther 5:2358–2365

    Article  PubMed  CAS  Google Scholar 

  • Brodeur GM, Maris JM (2006) Neuroblastoma. In: Pizzo, PA, and Poplack, DG, eds. Principles and practices of pediatric oncology, 5th edn. JB Lippincott Company, Philadelphia, PA

    Google Scholar 

  • Burkhart CA, Watt F, Murray J, Pajic M, Prokvolit A, Xue C, Flemming C, Smith J, Purmal A, Isachenko N, Komarov PG, Gurova KV, Sartorelli AC, Marshall GM, Norris MD, Gudkov AV, Haber M (2009) Small-molecule multidrug resistance-associated protein 1 inhibitor reversan increases the therapeutic index of chemotherapy in mouse models of neuroblastoma. Cancer Res 69:6573–6580

    Article  PubMed  CAS  Google Scholar 

  • Carr-Wilkinson J, O’Toole K, Wood KM, Challen CC, Baker AG, Board JR, Evans L, Cole M, Cheung NK, Boos J, Kohler G, Leuschner I, Pearson AD, Lunec J, Tweddle DA (2010) High frequency of p53/MDM2/p14ARF pathway abnormalities in relapsed neuroblastoma. Clin Cancer Res 16:1108–1118

    Article  PubMed  CAS  Google Scholar 

  • Chen Z, Lin Y, Barbieri E, Burlingame S, Hicks J, Ludwig A, Shohet JM (2009) Mdm2 deficiency suppresses MYCN-Driven neuroblastoma tumorigenesis in vivo. Neoplasia 11:753–762

    PubMed  CAS  Google Scholar 

  • Chesler L, Goldenberg DD, Collins R, Grimmer M, Kim GE, Tihan T, Nguyen K, Yakovenko S, Matthay KK, Weiss WA (2008) Chemotherapy-induced apoptosis in a transgenic model of neuroblastoma proceeds through p53 induction. Neoplasia 10:1268–1274

    PubMed  CAS  Google Scholar 

  • Flahaut M, Meier R, Coulon A, Nardou KA, Niggli FK, Martinet D, Beckmann JS, Joseph JM, Muhlethaler-Mottet A, Gross N (2009) The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/beta-catenin pathway. Oncogene 28:2245–2256

    Article  PubMed  CAS  Google Scholar 

  • Goldsmith KC, Hogarty MD (2005) Targeting programmed cell death pathways with experimental therapeutics: opportunities in high-risk neuroblastoma. Cancer Lett 228:133–141

    Article  PubMed  CAS  Google Scholar 

  • Goldstein LJ, Fojo AT, Ueda K, Crist W, Green A, Brodeur G, Pastan I, Gottesman MM (1990) Expression of the multidrug resistance, MDR1, gene in neuroblastomas. J Clin Oncol 8:128–136

    PubMed  CAS  Google Scholar 

  • Haber M, Smith J, Bordow SB, Flemming C, Cohn SL, London WB, Marshall GM, Norris MD (2006) Association of high-level MRP1 expression with poor clinical outcome in a large prospective study of primary neuroblastoma. J Clin Oncol 24:1546–1553

    Article  PubMed  CAS  Google Scholar 

  • Henderson MJ, Haber M, Porro A, Munoz MA, Iraci N, Xue C, Murray J, Flemming CL, Smith J, Fletcher JI, Gherardi S, Kwek CK, Russell AJ, Valli E, London WB, Buxton AB, Ashton LJ, Sartorelli AC, Cohn SL, Schwab M, Marshall GM, Perini G, Norris MD (2011) ABCC Multidrug transporters in childhood neuroblastoma: clinical and biological effects independent of cytotoxic drug efflux. J Natl Cancer Inst 103:1236–1251

    Article  PubMed  CAS  Google Scholar 

  • Houghton PJ, Morton CL, Tucker C, Payne D, Favours E, Cole C, Gorlick R, Kolb EA, Zhang W, Lock R, Carol H, Tajbakhsh M, Reynolds CP, Maris JM, Courtright J, Keir ST, Friedman HS, Stopford C, Zeidner J, Wu J, Liu T, Billups CA, Khan J, Ansher S, Zhang J, Smith MA (2007) The pediatric preclinical testing program: description of models and early testing results. Pediatr Blood Cancer 49:928–940

    Article  PubMed  Google Scholar 

  • Huang Y, Sadee W (2006) Membrane transporters and channels in chemoresistance and sensitivity of tumor cells. Cancer Lett 239:168–182

    Article  PubMed  CAS  Google Scholar 

  • Ishida S, McCormick F, Smith-McCune K, Hanahan D (2010) Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell 17:574–583

    Article  PubMed  CAS  Google Scholar 

  • Keshelava N, Zuo JJ, Chen P, Waidyaratne SN, Luna MC, Gomer CJ, Triche TJ, Reynolds CP (2001) Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines. Cancer Res 61:6185–6193

    PubMed  CAS  Google Scholar 

  • Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10:375–388

    Article  PubMed  CAS  Google Scholar 

  • Le MT, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V, Lodish HF, Lim B (2009) MicroRNA-125b is a novel negative regulator of p53. Genes Dev 23:862–876

    Article  PubMed  CAS  Google Scholar 

  • Leggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, Mercer KE, Zhuang Y, Panetta JC, Johnston B, Scheper RJ, Stewart CF, Schuetz JD (2004) Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol 24:7612–7621

    Article  PubMed  CAS  Google Scholar 

  • Lestini BJ, Goldsmith KC, Fluchel MN, Liu X, Chen NL, Goyal B, Pawel BR, Hogarty MD (2009) Mcl1 downregulation sensitizes neuroblastoma to cytotoxic chemotherapy and small molecule Bcl2-family antagonists. Cancer Biol Ther 8:1587–1595

    Article  PubMed  CAS  Google Scholar 

  • Lock R, Carol H, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP, Maris JM, Keir ST, Wu J, Smith MA (2008) Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr Blood Cancer 50:1181–1189

    Article  PubMed  Google Scholar 

  • Lorico A, Rappa G, Finch RA, Yang D, Flavell RA, Sartorelli AC (1997) Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione. Cancer Res 57:5238–5242

    PubMed  CAS  Google Scholar 

  • Maris JM (2010) Recent advances in neuroblastoma. N Engl J Med 362:2202–2211

    Article  PubMed  CAS  Google Scholar 

  • Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma. Lancet 369:2106–2120

    Article  PubMed  CAS  Google Scholar 

  • Matthay KK, Brisse H, Couanet D, Couturier J, Benard J, Mosseri V, Edeline V, Lumbroso J, Valteau-Couanet D, Michon J (2003) Central nervous system metastases in neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer 98:155–165

    Article  PubMed  Google Scholar 

  • Norris MD, Smith J, Tanabe K, Tobin P, Flemming C, Scheffer GL, Wielinga P, Cohn SL, London WB, Marshall GM, Allen JD, Haber M (2005) Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro. Mol Cancer Ther 4:547–553

    Article  PubMed  CAS  Google Scholar 

  • Oberthuer A, Berthold F, Warnat P, Hero B, Kahlert Y, Spitz R, Ernestus K, Konig R, Haas S, Eils R, Schwab M, Brors B, Westermann F, Fischer M (2006) Customized oligonucleotide microarray gene expression-based classification of neuroblastoma patients outperforms current clinical risk stratification. J Clin Oncol 24:5070–5078

    Article  PubMed  CAS  Google Scholar 

  • Okabe M, Szakacs G, Reimers MA, Suzuki T, Hall MD, Abe T, Weinstein JN, Gottesman MM (2008) Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters. Mol Cancer Ther 7:3081–3091

    Article  PubMed  CAS  Google Scholar 

  • Porro A, Haber M, Diolaiti D, Iraci N, Henderson M, Gherardi S, Valli E, Munoz MA, Xue C, Flemming C, Schwab M, Wong JH, Marshall GM, Della Valle G, Norris MD, Perini G (2010) Direct and coordinate regulation of ATP-binding cassette transporter genes by Myc factors generates specific transcription signatures that significantly affect the chemoresistance phenotype of cancer cells. J Biol Chem 285:19532–19543

    Article  PubMed  CAS  Google Scholar 

  • Schwickart M, Huang X, Lill JR, Liu J, Ferrando R, French DM, Maecker H, O’Rourke K, Bazan F, Eastham-Anderson J, Yue P, Dornan D, Huang DC, Dixit VM (2010) Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463:103–107

    Article  PubMed  CAS  Google Scholar 

  • Swarbrick A, Woods SL, Shaw A, Balakrishnan A, Phua Y, Nguyen A, Chanthery Y, Lim L, Ashton LJ, Judson RL, Huskey N, Blelloch R, Haber M, Norris MD, Lengyel P, Hackett CS, Preiss T, Chetcuti A, Sullivan CS, Marcusson EG, Weiss W, L’Etoile N, Goga A (2010) miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma. Nat Med 16:1134–1140

    Article  PubMed  CAS  Google Scholar 

  • Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234

    Article  PubMed  CAS  Google Scholar 

  • Tweddle DA, Malcolm AJ, Bown N, Pearson AD, Lunec J (2001) Evidence for the development of p53 mutations after cytotoxic therapy in a neuroblastoma cell line. Cancer Res 61:8–13

    PubMed  CAS  Google Scholar 

  • Valsesia-Wittmann S, Magdeleine M, Dupasquier S, Garin E, Jallas AC, Combaret V, Krause A, Leissner P, Puisieux A (2004) Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell 6:625–630

    Article  PubMed  CAS  Google Scholar 

  • Van Maerken T, Ferdinande L, Taildeman J, Lambertz I, Yigit N, Vercruysse L, Rihani A, Michaelis M, Cinatl J Jr., Cuvelier CA, Marine JC, De Paepe A, Bracke M, Speleman F, Vandesompele J (2009) Antitumor activity of the selective MDM2 antagonist nutlin-3 against chemoresistant neuroblastoma with wild-type p53. J Natl Cancer Inst 101:1562–1574

    Article  PubMed  Google Scholar 

  • Vassilev LT (2007) MDM2 inhibitors for cancer therapy. Trends Mol Med 13:23–31

    Article  PubMed  CAS  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310

    Article  PubMed  CAS  Google Scholar 

  • Weiss W, Aldape K, Mohapatra G, Feuerstein B, Bishop J (1997) Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J 16:2985–2995

    Article  PubMed  CAS  Google Scholar 

  • Wijnholds J, Evers R, van Leusden MR, Mol CA, Zaman GJ, Mayer U, Beijnen JH, van der Valk M, Krimpenfort P, Borst P (1997) Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nat Med 3:1275–1279

    Article  PubMed  CAS  Google Scholar 

  • Xue C, Haber M, Flemming C, Marshall GM, Lock RB, MacKenzie KL, Gurova KV, Norris MD, Gudkov AV (2007) p53 determines multidrug sensitivity of childhood neuroblastoma. Cancer Res 67:10351–10360

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia

    Jamie I. Fletcher, Michelle Haber, Michelle J. Henderson & Murray D. Norris

Authors
  1. Jamie I. Fletcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michelle Haber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michelle J. Henderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Murray D. Norris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jamie I. Fletcher .

Editor information

Editors and Affiliations

  1. , Kean University, Room 213, Library building, Morris Avenue 1000, Union, 07083, New Jersey, USA

    M.A. Hayat

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Fletcher, J.I., Haber, M., Henderson, M.J., Norris, M.D. (2012). Targeting Multidrug Resistance in Neuroblastoma. In: Hayat, M. (eds) Neuroblastoma. Pediatric Cancer, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2418-1_11

Download citation

Publish with us

Policies and ethics

Search

Navigation