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Identification of Smac mimetics as novel substrates for p-glycoprotein

Manuela Hugle1, Sebastian Czaplinski1, Karoline Habermann1

  • 1Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, 60528, Frankfurt, Germany.

Cancer Letters
|October 13, 2018
PubMed

Insights

Multidrug resistance (MDR) in pediatric cancer involves p-glycoprotein, which exports drugs. This study found Smac mimetics are also exported by p-glycoprotein, suggesting new therapeutic strategies.

Area of Science:

  • Oncology
  • Cancer Biology
  • Pharmacology

Background:

  • Multidrug resistance (MDR) hinders chemotherapy effectiveness in various cancers, including pediatric tumors.
  • High p-glycoprotein expression in cancer cells often drives MDR by exporting chemotherapeutic drugs.
  • Pediatric cancer cells were studied to understand acquired resistance mechanisms.

Purpose of the Study:

  • To investigate the role of p-glycoprotein in acquired chemoresistance in pediatric cancer cells.
  • To determine if novel therapeutics, Smac mimetics, are affected by p-glycoprotein-mediated MDR.
  • To explore potential therapeutic strategies combining Smac mimetics with p-glycoprotein inhibitors.

Main Methods:

  • Generation of pediatric cancer cells with acquired resistance to vincristine (VCR).
  • Assessment of p-glycoprotein expression levels in VCR-resistant cells.
  • Testing cross-resistance profiles of VCR-resistant cells against various chemotherapeutics and Smac mimetics.
  • Evaluating the effect of p-glycoprotein inhibitors on Smac mimetic sensitivity.

Main Results:

  • Vincristine-resistant pediatric cancer cells exhibited increased p-glycoprotein expression and a multidrug-resistant phenotype.
  • These cells showed cross-resistance to doxorubicin and etoposide, consistent with MDR.
  • Notably, VCR-resistant cells displayed cross-resistance to several Smac mimetics.
  • Resistance to Smac mimetics was reversed by p-glycoprotein inhibitors, indicating Smac mimetics are p-glycoprotein substrates.

Conclusions:

  • P-glycoprotein mediates resistance to Smac mimetics in pediatric cancer cells.
  • Smac mimetics are identified as novel substrates for p-glycoprotein.
  • Findings may inform clinical trial design, suggesting combinations of Smac mimetics with p-glycoprotein inhibitors to overcome MDR.
Keywords:
BV6Inhibitor of apoptosis proteinsMultidrug resistanceSmac mimeticsp-Glycoprotein

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