This study sought to characterize the activity of JNJ-26854165 (serdemetan) activity in models of mantle cell lymphoma (MCL) and multiple myeloma (MM). MM and MCL cells had decreased cholesterol efflux, and electron microscopy demonstrated the accumulation of lipid whorls, confirming the lysosomal storage disease phenotype. JNJ-26854165 induced induction of cholesterol regulatory genes sterol regulatory element-binding transcription factor-1 and -2 and liver X receptors α and β, along with increased expression of Niemann-Pick disease type-C1 and -C2. However, JNJ-26854165 induced enhanced subfamily A member-1 (ABCA1) turnover despite enhancing transcription. Finally, ABCA1 depletion resulted in enhanced sensitivity to JNJ-26854165. Overall, these findings support the hypothesis that serdemetan functions in part by inhibiting cholesterol transport.
See article at J Pharmacol Exp Ther 2013, 346:381–392.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics