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Oncotarget. 2014 Nov 15;5(21):10237-50.

Preclinical efficacy of sepantronium bromide (YM155) in multiple myeloma is conferred by down regulation of Mcl-1.

Author information

1
Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
2
Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
3
Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
4
INSERM U1040, Montpellier, France.
5
Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
6
National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
7
Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
8
INSERM U1040, Montpellier, France. CHU Montpellier, Institute of Research in Biotherapy, Montpellier, France.
9
Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.

Abstract

The inhibitor-of-apoptosis family member survivin has been reported to inhibit apoptosis and regulate mitosis and cytokinesis. In multiple myeloma, survivin has been described to be involved in downstream sequelae of various therapeutic agents. We assessed 1093 samples from previously untreated patients, including two independent cohorts of 392 and 701 patients, respectively. Survivin expression was associated with cell proliferation, adverse prognostic markers, and inferior event-free and overall survival, supporting the evaluation of survivin as a therapeutic target in myeloma. The small molecule suppressant of survivin--YM155--is in clinical development for the treatment of solid tumors. YM155 potently inhibited proliferation and induced apoptosis in primary myeloma cells and cell lines. Gene expression and protein profiling revealed the critical roles of IL6/STAT3-signaling and the unfolded protein response in the efficacy of YM155. Both pathways converged to down regulate anti-apoptotic Mcl-1 in myeloma cells. Conversely, growth inhibition and apoptotic cell death by YM155 was rescued by ectopic expression of Mcl-1 but not survivin, identifying Mcl-1 as the pivotal downstream target of YM155 in multiple myeloma. Mcl-1 expression was likewise associated with adverse prognostic markers, and inferior survival. Our results strongly support the clinical evaluation of YM155 in patients with multiple myeloma.

PMID:
25296978
PMCID:
PMC4279369
DOI:
10.18632/oncotarget.2529
[Indexed for MEDLINE]
Free PMC Article

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