Probenecid Sensitizes Neuroblastoma Cancer Stem Cells to Cisplatin

Cancer Invest. 2016;34(3):155-66. doi: 10.3109/07357907.2016.1139717. Epub 2016 Mar 10.

Abstract

We used both in vitro cultures of neuroblastoma cell lines and nude-mice xenotransplants to explore the effects of co-administration of cisplatin and probenecid. Probenecid sensitized neuroblastoma cells, including tumor cells with stem features, to the effects of cisplatin, both in vitro and in vivo. This effect was mediated by an increase in the apoptotic cell death and a concomitant decrease in cell proliferation. This effect is accompanied by modulation of the mRNA and protein of the drug efflux transporters MDR1, MRP2, and BCRP. The co-administration of probenecid with cisplatin should be explored as a possible therapeutic strategy.

Keywords: Chemotherapy; Efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / administration & dosage
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression
  • Humans
  • Mice, Nude
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / physiology
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Probenecid / administration & dosage
  • Side-Population Cells / drug effects
  • Side-Population Cells / physiology
  • Xenograft Model Antitumor Assays

Substances

  • ABCB1 protein, human
  • ABCC2 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • CASP3 protein, human
  • Caspase 3
  • Probenecid
  • Cisplatin