Proteasome inhibition correlates with intracellular bortezomib concentrations but not with antiproliferative effects after bolus treatment in myeloma cell lines

• Verfasst von: Dettmer, Susan [VerfasserIn]
• Verfasst von: Theile, Dirk [VerfasserIn]
• Verfasst von: Schäfer, Julia [VerfasserIn]
• Verfasst von: Seckinger, Anja [VerfasserIn]
• Verfasst von: Burhenne, Jürgen [VerfasserIn]
• Verfasst von: Weiß, Johanna [VerfasserIn]
• Titel: Proteasome inhibition correlates with intracellular bortezomib concentrations but not with antiproliferative effects after bolus treatment in myeloma cell lines
• Verf.angabe: Susan Dettmer, Dirk Theile, Julia Schäfer, Anja Seckinger, Jürgen Burhenne, Johanna Weiss
• Umfang: 11 S.
• Fussnoten: Gesehen am 04.12.2017
• Titel Quelle: Enthalten in: Naunyn-Schmiedeberg's archives of pharmacology
• Jahr Quelle: 2016
• Band/Heft Quelle: 389(2016), 10, S. 1091-1101
• ISSN Quelle: 1432-1912
• DOI: doi:10.1007/s00210-016-1276-9
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1566019494

Abstract

Although bortezomib is successfully used against multiple myeloma, the pharmacodynamics of proteasome inhibition and its association with efficacy or resistance is poorly understood. Using ultra performance liquid chromatography coupled to tandem mass spectrometry, site-specific luminogenic substrate assays and 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide (MTT) assays, effects of bortezomib on cellular drug concentrations, chymotrypsin- , caspase- , and trypsin-like activities, and cytotoxic efficacy were evaluated in eight myeloma cell lines directly after 1 h of exposure and additionally after a 23-h washout phase. Bortezomib accumulated in myeloma cells by up to 100-fold and concentration-dependently inhibited the proteasomal activities with the chymotrypsin-like activity being the most sensitive. Whereas intracellular concentrations correlated with the inhibition of the chymotrypsin- and the caspase-like activities of the proteasome, the cytotoxic efficacy of bortezomib did not correlate with either intracellular concentrations or proteasomal inhibition. However, the ratio of concentrations measured directly after the exposure and after the washout phase (indicating drug disposition) correlated with efficacy, suggesting that the cell’s ability to dispose bortezomib at least in part influences bortezomib’s cytotoxicity. In conclusion, this data argues against a direct association of intracellular concentration or proteasomal inhibition with cytotoxic efficacy but advocates for an important role of cellular drug disposition. Moreover, this study underlines the pleiotropic mode of action of bortezomib going beyond proteasome inhibition.