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Carfilzomib resistance due to ABCB1/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma
- Source :
- Leukemia, 32(2), 391-401, Leukemia, Leukemia, 32, 391-401
- Publication Year :
- 2018
-
Abstract
- Proteasome inhibitor (PI) carfilzomib (CFZ) has activity superior to bortezomib (BTZ) and is increasingly incorporated in multiple myeloma (MM) frontline therapy and relapsed settings. Most MM patients ultimately experience PI-refractory disease, an unmet medical need with poorly understood biology and dismal outcome. Pharmacologic targeting of ABCB1 improved patient outcomes, including MM, but suffered from adverse drug effects and insufficient plasma concentrations. Proteomics analysis identified ABCB1 overexpression as the most significant change in CFZ-resistant MM cells. We addressed the functional role of ABCB1 overexpression in MM and observed significantly upregulated ABCB1 in peripheral blood malignant plasma cells (PCs) vs untreated patients' bone marrow PC. ABCB1 overexpression reduces the proteasome-inhibiting activity of CFZ due to drug efflux, in contrast to BTZ. Likewise, the cytotoxicity of established anti-MM drugs was significantly reduced in ABCB1-expressing MM cells. In search for potential drugs targeting ABCB1 in clinical trials, we identified the HIV protease inhibitors nelfinavir (NFV) and lopinavir (LPV) as potent functional modulators of ABCB1-mediated drug export, most likely via modulation of mitochondria permeability transition pore. NFV and LPV restored CFZ activity at therapeutically relevant drug levels and thus represent ready-to-use drugs to be tested in clinical trials to target ABCB1 and to re-sensitize PC to established myeloma drugs, in particular CFZ.
- Subjects :
- 0301 basic medicine
Drug
Cancer Research
Proteasome Endopeptidase Complex
Drug export
ATP Binding Cassette Transporter, Subfamily B
media_common.quotation_subject
Plasma Cells
Antineoplastic Agents
Pharmacology
Lopinavir
Bortezomib
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Line, Tumor
medicine
Humans
Multiple myeloma
media_common
Nelfinavir
business.industry
Hematology
HIV Protease Inhibitors
medicine.disease
Carfilzomib
3. Good health
030104 developmental biology
Oncology
chemistry
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Proteasome inhibitor
Original Article
business
Multiple Myeloma
Oligopeptides
Proteasome Inhibitors
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Leukemia, 32(2), 391-401, Leukemia, Leukemia, 32, 391-401
- Accession number :
- edsair.doi.dedup.....90a229c7e0897de13d268e58d34d9817