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

Abstract

The aim of this study is to determine whether manipulation of the drug transporter Pglycoprotein improves the efficacy of proteasome inhibitors in multiple myeloma cells. Pglycoprotein is a well-known drug transporter that is associated with chemotherapy resistance in a number of cancers but its role in modulating the efficacy of proteasome inhibitors in multiple myeloma is not well understood. Research has shown that the second generation proteasome inhibitor carfilzomib is a substrate of P-glycoprotein and as such its efficacy may correlate with P-glycoprotein activity. In contrast to carfilzomib, research concerning the first-in-class proteasome inhibitor bortezomib is inconsistent with some reports suggesting that inhibition of P-glycoprotein increases bortezomib cytotoxicity in multiple myeloma cells whereas others have shown no effect. Through the mining of publicly available gene expression microarrays of patient bone marrow, we show that P-glycoprotein gene expression increases with the disease stages leading to multiple myeloma. However, RNA-seq on LP-1 cells treated with bortezomib or carfilzomib demonstrated minimal basal P-glycoprotein expression which did not increase with treatment. Moreover, 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 hypothesised that by inhibiting P-glycoprotein, multiple myeloma cell sensitivity to proteasome inhibitors would increase, thus providing a potential approach to improving responses and reversing resistance to these agents. However, the sensitivity of multiple myeloma cells lines to proteasome inhibition was not enhanced by inhibition of P-glycoprotein with the specific inhibitor tariquidar. In addition, targeting glucosylceramide synthase with eliglustat did not inhibit P-glycoprotein activity and also did not improve proteasome inhibitor efficacy except at a high concentration. We conclude that P-glycoprotein is poorly expressed in multiple myeloma cells, its inhibition does not enhance .

Prognostic and predictive biomarker developments in multiple myeloma

“…Controversy also surrounds the expression level of CD38 on MM plasma cells and responses to anti-CD38 monoclonal antibodies such as daratumumab, which are efficacious even when cell surface expression is low [4]. Similarly, mechanisms of resistance to proteasome inhibitors are still not well understood, with mutations in proteasome subunits or expression of multi-drug resistance transporters evident in only a minority of cases and of questionable involvement [4,[92][93][94]. Recently, the poor prognostic impact of desmoglein-2 on the malignant plasma cells of newly diagnosed MM patients has been demonstrated with efforts underway to elucidate its biological role in MM and to develop targeted therapeutics [95].…”

Role of Sphingolipids in Multiple Myeloma Progression, Drug Resistance, and Their Potential as Therapeutic Targets

“…However, it’s unclear if the upregulation of ABCB1 in these cells results from increased GCS. Further, it was reported that the GCS inhibitor eliglustat did not induce ABCB1 protein on the cell surface in the KMS-18 MM cell line ( 199 ). Fu et al.…”

“…There is controversy about whether bortezomib is a ABCB1 substrate, but carfilzomib is, and therefore MM cells with increased ABCB1 are more carfilzomib resistant. However, in many MM cell lines, ABCB1 expression is very low on the cell surface, and the specific ABCB1 inhibitor tariquidar did not enhance the sensitivity to either bortezomib or carfilzomib, so the relevance to MM biology and proteasome inhibitor resistance is unclear ( 199 ). A few studies suggest that ABCG2 in MM cells may contribute to intrinsic drug resistance, which is increased when the cells are exposed to ABCG2 substrates such as doxorubicin or topotecan ( 200 , 201 ).…”

Drug and Solute Transporters in Mediating Resistance to Novel Therapeutics in Multiple Myeloma

“…It is generally agreed that bortezomib is a poor substrate of P-gp. ,− Similar to lenalidomide, however, there is conflict in the literature regarding this drug; some researchers have shown that genetic or pharmacological inhibition of P-gp increases MM and other cancer cell sensitivity to bortezomib (Table ). ,, …”