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3 results on '"Tiedemann RE"'

1. Getting to the root of the problem: the causes of relapse in multiple myeloma.

Author

Chan Chung KC and Tiedemann RE

Subjects
Disease Progression, Drug Resistance, Neoplasm, Humans, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Neoplastic Stem Cells metabolism, Recurrence, Antineoplastic Agents pharmacology, Multiple Myeloma pathology, Proteasome Inhibitors pharmacology
Abstract

Multiple myeloma (MM) remains incurable, and ultimately, patients exhibit disease progression under current treatment regimens. Proteasome inhibitors have emerged as frontline treatment of relapsed and refractory MM however, resistance to these drugs occur through poorly defined mechanisms. Numerous studies have identified different acquired resistance models such as β5 proteasome subunit mutations and stabilization of tumor suppressors and apoptotic proteins. In addition, recent findings have identified a progenitor organization in MM whereby early progenitor tumor cells show resistance to proteasome inhibitor therapy and cause progressive disease with maturation arrest. This editorial highlights the potential causes of MM relapse in the context of these tumor progenitor cells and the role these cells play in treatment failure.

Published
2014
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2. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma.

Author

Leung-Hagesteijn C, Erdmann N, Cheung G, Keats JJ, Stewart AK, Reece DE, Chung KC, and Tiedemann RE

Subjects
Activating Transcription Factor 6 metabolism, Boronic Acids pharmacology, Boronic Acids therapeutic use, Bortezomib, Cell Survival drug effects, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Endoplasmic Reticulum Stress, Endoribonucleases metabolism, Humans, Immunophenotyping, Membrane Proteins metabolism, Multiple Myeloma metabolism, Mutation, Plasma Cells metabolism, Plasma Cells pathology, Precursor Cells, B-Lymphoid metabolism, Precursor Cells, B-Lymphoid pathology, Proteasome Inhibitors pharmacology, Protein Serine-Threonine Kinases metabolism, Pyrazines pharmacology, Pyrazines therapeutic use, Regulatory Factor X Transcription Factors, Signal Transduction, Transcription Factors genetics, Transcription Factors metabolism, X-Box Binding Protein 1, eIF-2 Kinase metabolism, DNA-Binding Proteins deficiency, Drug Resistance, Neoplasm genetics, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Proteasome Inhibitors therapeutic use, Transcription Factors deficiency
Abstract

Proteasome inhibitor (PI) resistance mechanisms in multiple myeloma (MM) remain controversial. We report the existence of a progenitor organization in primary MM that recapitulates maturation stages between B cells and plasma cells and that contributes to clinical PI resistance. Xbp1s(-) tumor B cells and pre-plasmablasts survive therapeutic PI, preventing cure, while maturation arrest of MM before the plasmablast stage enables progressive disease on PI treatment. Mechanistically, suppression of Xbp1s in MM is shown to induce bortezomib resistance via de-commitment to plasma cell maturation and immunoglobulin production, diminishing endoplasmic reticulum (ER) front-loading and cytotoxic susceptibility to PI-induced inhibition of ER-associated degradation. These results reveal the tumor progenitor structure in MM and highlight its role in therapeutic failure., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Published
2013
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3. Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo.

Author

Tiedemann RE, Schmidt J, Keats JJ, Shi CX, Zhu YX, Palmer SE, Mao X, Schimmer AD, and Stewart AK

Subjects
Animals, Antineoplastic Agents chemistry, Apoptosis drug effects, Biological Products chemistry, Bone Marrow Cells cytology, Bone Marrow Cells drug effects, Cell Lineage, Cells, Cultured, Chymases metabolism, Coculture Techniques, Combinatorial Chemistry Techniques, Cyclin D, Cyclins genetics, Cyclins metabolism, Drug Screening Assays, Antitumor, Enzyme Activation drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Molecular Structure, Multiple Myeloma pathology, NF-kappa B metabolism, Pentacyclic Triterpenes, Proteasome Endopeptidase Complex metabolism, Transcriptional Activation drug effects, Triterpenes chemistry, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Biological Products pharmacology, Chymases antagonists & inhibitors, Multiple Myeloma metabolism, NF-kappa B antagonists & inhibitors, Proteasome Inhibitors, Triterpenes pharmacology
Abstract

As multiple myeloma tumors universally dysregulate cyclin D genes we conducted high-throughput chemical library screens for compounds that induce suppression of cyclin D2 promoter transcription. The top-ranked compound was a natural triterpenoid, pristimerin. Strikingly, the early transcriptional response of cells treated with pristimerin closely resembles cellular responses elicited by proteosome inhibitors, with rapid induction of heat shock proteins, activating transcription factor 3 (ATF3), and CHOP. Enzymatic assays and immunoblotting confirm that pristimerin rapidly (< 90 minutes) and specifically inhibits chymotrypsin-like proteosome activity at low concentrations (< 100 nM) and causes accumulation of cellular ubiquitinated proteins. Notably, cytotoxic triterpenoids including pristimerin inhibit NF-kappaB activation via inhibition of IKK alpha or IKK beta, whereas proteosome inhibitors instead suppress NF-kappaB function by impairing degradation of ubiquitinated I kappaB. By inhibiting both IKK and the proteosome, pristimerin causes overt suppression of constitutive NF-kappaB activity in myeloma cells that may mediate its suppression of cyclin D. Multiple myeloma is exquisitely sensitive to proteosome or NF-kappaB pathway inhibition. Consistent with this, pristimerin is potently and selectively lethal to primary myeloma cells (IC(50) < 100 nM), inhibits xenografted plasmacytoma tumors in mice, and is synergistically cytotoxic with bortezomib--providing the rationale for pharmaceutical development of triterpenoid dual-function proteosome/NF-kappaB inhibitors as therapeutics for human multiple myeloma and related malignancies.

Published
2009
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