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Updated: Jun 25, 2026
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Role of active drug transporters in refractory multiple myeloma
Marco Tucci1, Cosima Quatraro, Franco Dammacco
1DIMO, Department of Internal Medicine and Clinical Oncology, University of Bari, Italy. m.tucci@dimo.uniba.it
Abstract:
Drug resistance is a major drawback for cancer chemotherapy protocols and previous studies have demonstrated the overexpression of the P-glycoprotein (P-gp) as mechanism by which myeloma cells develop multidrug resistance (MDR). However, other molecules may apparently promote MDR in multiple myeloma (MM). They include both lung resistance-related protein (LRP) and p53 activation. The inhibition of P-gp in MM patients treated with melphalan (PAM) has been associated to increased toxicity, whereas defective apoptosis due to down-modulation of the NF-kB is a feature of MDR+ myeloma cells. On the contrary, clinical trials with proteasome inhibitors have been successfully carried out to overcome MDR despite their toxicity profile. Recently, sigma receptors (sigmaR)(S), namely sigmaR(1) and sigmaR(2), have been found to be overexpressed in breast cancer cells. In addition, their levels correlate with both P-gp upregulation and MDR development. By contrast, selective inhibitors of sigmaR(S) as PB28, disrupt the P-gp signals and restore the apoptosis machinery in malignant cells. We have reviewed the major pathogenetic events promoting MDR in MM and focused on the sigmaR(S) as potential mechanism driving this function. We demonstrate that MDR+ myeloma cells overexpress the sigmaR(2) and that the treatment with PB28 induces P-gp down-modulation through the activation of the caspases enrolled in both extrinsic and intrinsic apoptotic pathways. Thus, sigmaR(2) inhibitors may be tentatively proposed for the treatment of PAM-resistant MM patients.
Insights
Multidrug resistance (MDR) in multiple myeloma (MM) involves P-glycoprotein (P-gp). Sigma receptors (sigmaR), particularly sigmaR(2), are overexpressed in MDR+ MM cells. Inhibiting sigmaR(2) with PB28 down-regulates P-gp and restores apoptosis, offering a potential treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Drug resistance is a significant challenge in cancer chemotherapy, particularly in multiple myeloma (MM).
- P-glycoprotein (P-gp) overexpression is a known mechanism for multidrug resistance (MDR) in MM, but other factors like lung resistance-related protein (LRP) and p53 activation also contribute.
- Defective apoptosis due to NF-kB down-modulation is observed in MDR+ myeloma cells, while proteasome inhibitors show promise in overcoming MDR despite toxicity.
Purpose of the Study:
- To review the key pathogenetic events driving MDR in multiple myeloma (MM).
- To investigate the role of sigma receptors (sigmaR), specifically sigmaR(2), as a potential mechanism in MM multidrug resistance (MDR).
- To evaluate the efficacy of sigmaR(2) inhibition using PB28 in modulating P-gp and restoring apoptosis in MM cells.
Main Methods:
- Literature review of major pathogenetic events promoting MDR in MM.
- Analysis of sigma receptor (sigmaR) expression in multidrug-resistant (MDR+) myeloma cells.
- Treatment of MDR+ myeloma cells with selective sigmaR(2) inhibitor PB28.
- Assessment of P-glycoprotein (P-gp) down-modulation and caspase activation (extrinsic and intrinsic apoptotic pathways).
Main Results:
- Multidrug-resistant (MDR+) myeloma cells exhibit overexpression of sigma receptor 2 (sigmaR(2)).
- Treatment with the sigmaR(2) inhibitor PB28 leads to the down-modulation of P-glycoprotein (P-gp).
- PB28 treatment activates caspases involved in both extrinsic and intrinsic apoptotic pathways, restoring the apoptosis machinery.
Conclusions:
- Sigma receptor 2 (sigmaR(2)) is implicated as a driver of multidrug resistance (MDR) in multiple myeloma (MM).
- Selective sigmaR(2) inhibitors, such as PB28, can overcome P-glycoprotein (P-gp)-mediated resistance by inducing apoptosis.
- SigmaR(2) inhibitors represent a potential therapeutic strategy for treating melphalan-resistant multiple myeloma (MM).
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