Cellular effect and efficacy of carfilzomib depends on cellular net concentration gradient
Purpose: The cellular interrelation between intracellular concentrations of unbound carfilzomib, a second-generation proteasome inhibitor, and subsequent proteasome inhibition and effect on cell viability are unknown and were evaluated for two different exposure regimens: A high dose bolus regime of...
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| Hauptverfasser: | , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
12 May 2017
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| In: |
Cancer chemotherapy and pharmacology
Year: 2017, Jahrgang: 80, Heft: 1, Pages: 71-79 |
| ISSN: | 1432-0843 |
| DOI: | 10.1007/s00280-017-3335-4 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1007/s00280-017-3335-4 Verlag, Volltext: https://doi.org/10.1007/s00280-017-3335-4 
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| Verfasserangaben: | Julia Schäfer, Lukas Welti, Anja Seckinger, Jürgen Burhenne, Dirk Theile, Johanna Weiss |
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| 245 | 1 | 0 | |a Cellular effect and efficacy of carfilzomib depends on cellular net concentration gradient |c Julia Schäfer, Lukas Welti, Anja Seckinger, Jürgen Burhenne, Dirk Theile, Johanna Weiss |
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| 520 | |a Purpose: The cellular interrelation between intracellular concentrations of unbound carfilzomib, a second-generation proteasome inhibitor, and subsequent proteasome inhibition and effect on cell viability are unknown and were evaluated for two different exposure regimens: A high dose bolus regime of 500 nM for 1 h followed by 47 h in drug-free media vs. 48-h continuous exposure to 10 nM. Methods: Eight multiple myeloma cell lines were exposed to either one of the two exposure regimens. We quantified the intracellular unbound carfilzomib fraction up to 48 h with a new ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) method. Intracellular concentrations were compared to simultaneously determined cell viability (AlamarBlue® assay) and proteasomal subunit activity (ProGlo™ assay).ResultsWithin the first 10 min, the proportional intracellular enrichment of unbound carfilzomib was higher (313 nM; 62.6%) for the exposure to 500 nM compared to 10 nM (1.93 nM; 19.3%). However, after 1 h, an intracellular/extracellular concentration equilibrium was reached with both settings. At low exposure concentrations, drug removal after 1 h diminished carfilzomib efficacy. Moreover, proteasomal activity recovered when exposed to 10 nM for 48 h. However, when exposure concentration was high (500 nM) proteasome inhibition was complete and sustained even with drug removal after 1 h.ConclusionsWe demonstrated that the carfilzomib concentration gradient determines cellular uptake kinetics. The uptake kinetics in turn affects binding, saturation, and activity of the proteasome. Together, these data underscore the importance of steep concentrations for the in vitro efficacy of carfilzomib. | ||
| 650 | 4 | |a Carfilzomib | |
| 650 | 4 | |a Cellular pharmacokinetics | |
| 650 | 4 | |a Concentration gradient | |
| 650 | 4 | |a Multiple myeloma | |
| 650 | 4 | |a Proteasome inhibition | |
| 650 | 4 | |a Tandem mass spectrometry | |
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