Inhibition of P-Glycoprotein Does Not Increase the Efficacy of Proteasome Inhibitors in Multiple Myeloma Cells

Rachel L. Mynott, Craig T. Wallington-Beddoe

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

P-Glycoprotein is a well-known drug transporter associated with chemotherapy resistance in a number of cancers, but its role in modulating proteasome inhibitor efficacy in multiple myeloma is not well understood. The second-generation proteasome inhibitor carfilzomib is thought to be a substrate of P-glycoprotein whose efficacy may correlate with P-glycoprotein activity; however, research concerning the first-in-class proteasome inhibitor bortezomib is inconsistent. We show that while P-glycoprotein gene expression increases with the disease stages leading to multiple myeloma it does not affect the survival of newly diagnosed patients treated with bortezomib. Moreover, RNA-seq on LP-1 cells demonstrated minimal basal P-glycoprotein expression which did not increase after exposure to bortezomib or carfilzomib. Only one (KMS-18) of nine multiple myeloma cell lines expressed P-glycoprotein, including RPMI-8226 cells that are resistant to bortezomib or carfilzomib. We hypothesized that by inhibiting P-glycoprotein multiple myeloma cell sensitivity to proteasome inhibitors would increase; however, the sensitivity of multiple myeloma cells lines to proteasome inhibition was not enhanced by the specific P-glycoprotein inhibitor tariquidar. In addition, targeting glucosylceramide synthase with eliglustat did not inhibit P-glycoprotein activity nor improve proteasome inhibitor efficacy except at a high concentration. To confirm these negative findings, tariquidar did not substantially increase the cytotoxicity of bortezomib or carfilzomib in P-glycoprotein-expressing K562/ADM cells. We conclude the following: P-glycoprotein expression may not correlate with the survival of newly diagnosed multiple myeloma patients treated with proteasome inhibitors. P-glycoprotein is poorly expressed in many multiple myeloma cell lines, and its inhibition does not appreciably enhance the efficacy of proteasome inhibitors.
Original languageEnglish
Pages (from-to)713-729
Number of pages17
JournalACS Pharmacology and Translational Science
Volume4
Issue number2
Early online date4 Feb 2021
DOIs
Publication statusPublished - 9 Apr 2021

Keywords

  • Multiple myeloma
  • Proteasome inhibitor
  • P-glycoprotein
  • Cells
  • Inhibitors
  • Inhibition
  • Peptides and proteins
  • Genetics
  • multiple myeloma
  • proteasome inhibitor

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