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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

The Novel Anticancer Agent JNJ-26854165 Induces Cell Death through Inhibition of Cholesterol Transport and Degradation of ABCA1

Richard J. Jones, Dongmin Gu, Chad C. Bjorklund, Isere Kuiatse, Alan T. Remaley, Tarig Bashir, Veronique Vreys and Robert Z. Orlowski
Journal of Pharmacology and Experimental Therapeutics September 2013, 346 (3) 381-392; DOI: https://doi.org/10.1124/jpet.113.204958
Richard J. Jones
The Department of Lymphoma and Myeloma (R.J.J., D.G., C.C.B., I.K., R.Z.O.) and the Department of Experimental Therapeutics (R.Z.O.), The University of Texas MD Anderson Cancer Center, Houston, Texas; Lipoprotein Metabolism Section, Cardiopulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (A.T.R.); and Oncology, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium (T.B., V.V.)
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Dongmin Gu
The Department of Lymphoma and Myeloma (R.J.J., D.G., C.C.B., I.K., R.Z.O.) and the Department of Experimental Therapeutics (R.Z.O.), The University of Texas MD Anderson Cancer Center, Houston, Texas; Lipoprotein Metabolism Section, Cardiopulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (A.T.R.); and Oncology, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium (T.B., V.V.)
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Chad C. Bjorklund
The Department of Lymphoma and Myeloma (R.J.J., D.G., C.C.B., I.K., R.Z.O.) and the Department of Experimental Therapeutics (R.Z.O.), The University of Texas MD Anderson Cancer Center, Houston, Texas; Lipoprotein Metabolism Section, Cardiopulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (A.T.R.); and Oncology, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium (T.B., V.V.)
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Isere Kuiatse
The Department of Lymphoma and Myeloma (R.J.J., D.G., C.C.B., I.K., R.Z.O.) and the Department of Experimental Therapeutics (R.Z.O.), The University of Texas MD Anderson Cancer Center, Houston, Texas; Lipoprotein Metabolism Section, Cardiopulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (A.T.R.); and Oncology, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium (T.B., V.V.)
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Alan T. Remaley
The Department of Lymphoma and Myeloma (R.J.J., D.G., C.C.B., I.K., R.Z.O.) and the Department of Experimental Therapeutics (R.Z.O.), The University of Texas MD Anderson Cancer Center, Houston, Texas; Lipoprotein Metabolism Section, Cardiopulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (A.T.R.); and Oncology, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium (T.B., V.V.)
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Tarig Bashir
The Department of Lymphoma and Myeloma (R.J.J., D.G., C.C.B., I.K., R.Z.O.) and the Department of Experimental Therapeutics (R.Z.O.), The University of Texas MD Anderson Cancer Center, Houston, Texas; Lipoprotein Metabolism Section, Cardiopulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (A.T.R.); and Oncology, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium (T.B., V.V.)
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Veronique Vreys
The Department of Lymphoma and Myeloma (R.J.J., D.G., C.C.B., I.K., R.Z.O.) and the Department of Experimental Therapeutics (R.Z.O.), The University of Texas MD Anderson Cancer Center, Houston, Texas; Lipoprotein Metabolism Section, Cardiopulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (A.T.R.); and Oncology, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium (T.B., V.V.)
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Robert Z. Orlowski
The Department of Lymphoma and Myeloma (R.J.J., D.G., C.C.B., I.K., R.Z.O.) and the Department of Experimental Therapeutics (R.Z.O.), The University of Texas MD Anderson Cancer Center, Houston, Texas; Lipoprotein Metabolism Section, Cardiopulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (A.T.R.); and Oncology, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium (T.B., V.V.)
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This article has a correction. Please see:

  • Correction to “The Novel Anti-Cancer Agent JNJ-26854165 Induces Cell Death through Inhibition of Cholesterol Transport and Degradation of ABCA1” - November 01, 2013

Abstract

JNJ-26854165 (serdemetan) has previously been reported to inhibit the function of the E3 ligase human double minute 2, and we initially sought to characterize its activity in models of mantle cell lymphoma (MCL) and multiple myeloma (MM). Serdemetan induced a dose-dependent inhibition of proliferation in both wild-type (wt) and mutant (mut) p53 cell lines, with IC50 values from 0.25 to 3 μM/l, in association with an S phase cell cycle arrest. Caspase-3 activation was primarily seen in wtp53-bearing cells but also occurred in mutp53-bearing cells, albeit to a lesser extent. 293T cells treated with JNJ-26854165 and serdemetan-resistant fibroblasts displayed accumulation of cholesterol within endosomes, a phenotype reminiscent of that seen in the ATP-binding cassette subfamily A member-1 (ABCA1) cholesterol transport disorder, Tangiers disease. 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, liver X receptors α and β, along with increased expression of Niemann-Pick disease type-C1 and -C2. However, JNJ-26854165 induced enhanced 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 and that this pathway is a potential new target for the treatment of MCL and MM.

Footnotes

    • Received March 20, 2013.
    • Accepted June 28, 2013.
  • This work was supported, in part, by the Lymphoma Research Foundation [Grant 120808] (to R.J.J., a Lymphoma Research Foundation Fellow); the National Institutes of Health National Cancer Institute [Grant P50 CA142509] (to R.Z.O. and R.J.J.); and the Intramural Research Program of the National Institutes of Health [National Heart, Lung, and Blood Institute] [Grant HL002058-18 CPB].

  • T.B. and V.V. are employees of Janssen Research & Development. R.Z.O. has served on an advisory board for Johnson & Johnson PRDU and received research funding from this entity.

  • dx.doi.org/10.1124/jpet.113.204958.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 346 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 3
1 Sep 2013
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

JNJ-26854165 Inhibits Cholesterol Transport

Richard J. Jones, Dongmin Gu, Chad C. Bjorklund, Isere Kuiatse, Alan T. Remaley, Tarig Bashir, Veronique Vreys and Robert Z. Orlowski
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 381-392; DOI: https://doi.org/10.1124/jpet.113.204958

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

JNJ-26854165 Inhibits Cholesterol Transport

Richard J. Jones, Dongmin Gu, Chad C. Bjorklund, Isere Kuiatse, Alan T. Remaley, Tarig Bashir, Veronique Vreys and Robert Z. Orlowski
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 381-392; DOI: https://doi.org/10.1124/jpet.113.204958
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