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Inhibition of P-Glycoprotein Does Not Increase the Efficacy of Proteasome Inhibitors in Multiple Myeloma Cells
Rachel L Mynott1, Craig T Wallington-Beddoe1,2,3,4
1College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia.
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.
Insights
P-glycoprotein (P-gp) expression does not impact survival for multiple myeloma patients on bortezomib. Inhibiting P-gp does not improve proteasome inhibitor efficacy in most multiple myeloma cell lines.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- P-glycoprotein (P-gp) is a drug transporter linked to chemotherapy resistance.
- Its role in multiple myeloma (MM) and response to proteasome inhibitors (PIs) like bortezomib and carfilzomib is unclear.
- P-gp is a potential target to overcome PI resistance.
Purpose of the Study:
- To investigate the correlation between P-glycoprotein expression and patient survival with bortezomib treatment.
- To determine if P-glycoprotein inhibition enhances the efficacy of proteasome inhibitors in multiple myeloma.
- To assess the expression of P-gp in multiple myeloma cell lines and its modulation by PIs.
Main Methods:
- Analysis of P-glycoprotein gene expression in relation to patient survival data.
- RNA sequencing of multiple myeloma cell lines (LP-1) after exposure to bortezomib and carfilzomib.
- Testing the efficacy of P-glycoprotein inhibitors (tariquidar, eliglustat) in combination with proteasome inhibitors on multiple myeloma cell lines.
- Cytotoxicity assays using P-glycoprotein-expressing K562/ADM cells.
Main Results:
- P-glycoprotein gene expression increased with multiple myeloma disease stage but did not affect survival in newly diagnosed patients treated with bortezomib.
- Minimal basal P-glycoprotein expression was observed in LP-1 cells, with no increase after bortezomib or carfilzomib exposure.
- Only one of nine MM cell lines (KMS-18) expressed P-glycoprotein; RPMI-8226 cells, resistant to bortezomib/carfilzomib, did not express P-gp.
- Inhibition of P-glycoprotein with tariquidar or eliglustat did not enhance multiple myeloma cell line sensitivity to proteasome inhibitors.
- Tariquidar did not significantly increase bortezomib or carfilzomib cytotoxicity in P-gp-expressing K562/ADM cells.
Conclusions:
- P-glycoprotein expression may not correlate with survival outcomes for multiple myeloma patients receiving proteasome inhibitors.
- P-glycoprotein is generally poorly expressed in multiple myeloma cell lines.
- Inhibiting P-glycoprotein does not substantially improve the efficacy of proteasome inhibitors in multiple myeloma.
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