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1.
Mol Cancer Ther ; 11(4): 942-51, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22246439

ABSTRACT

The NEDD8-activating enzyme is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases that regulate degradation of a distinct subset of proteins. The more targeted impact of NEDD8-activating enzyme on protein degradation prompted us to study MLN4924, an investigational NEDD8-activating enzyme inhibitor, in preclinical multiple myeloma models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability (EC(50) = 25-150 nmol/L) in a panel of human multiple myeloma cell lines. MLN4924 was similarly active against a bortezomib-resistant ANBL-6 subline and its bortezomib-sensitive parental cells. MLN4924 had submicromolar activity (EC(50) values <500 nmol/L) against primary CD138(+) multiple myeloma patient cells and exhibited at least additive effect when combined with dexamethasone, doxorubicin, and bortezomib against MM.1S cells. The bortezomib-induced compensatory upregulation of transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment, suggesting distinct functional roles of NEDD8-activating enzyme versus 20S proteasome. MLN4924 was well tolerated at doses up to 60 mg/kg 2× daily and significantly reduced tumor burden in both a subcutaneous and an orthotopic mouse model of multiple myeloma. These studies provide the framework for the clinical investigation of MLN4924 in multiple myeloma.


Subject(s)
Multiple Myeloma/drug therapy , Ubiquitin-Activating Enzymes/antagonists & inhibitors , Ubiquitins/antagonists & inhibitors , Animals , Boronic Acids/pharmacology , Bortezomib , Cell Line, Tumor , Gene Expression Profiling , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Multiple Myeloma/enzymology , Multiple Myeloma/genetics , NEDD8 Protein , Pyrazines/pharmacology , Treatment Outcome , Ubiquitin-Activating Enzymes/metabolism , Ubiquitination , Ubiquitins/metabolism , Xenograft Model Antitumor Assays
2.
Cell ; 146(6): 904-17, 2011 Sep 16.
Article in English | MEDLINE | ID: mdl-21889194

ABSTRACT

MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Multiple Myeloma/drug therapy , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Azepines/chemistry , Azepines/pharmacology , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Cell Line, Tumor , Disease Models, Animal , Humans , Mice , Nuclear Proteins/chemistry , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Protein Structure, Tertiary , Proto-Oncogene Proteins c-myc/genetics , Transcriptional Activation/drug effects , Triazoles/chemistry , Triazoles/pharmacology
3.
J Clin Endocrinol Metab ; 92(12): 4845-52, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17848408

ABSTRACT

CONTEXT: The Bcl-2 family of proteins regulates apoptosis in various models and may represent a promising therapeutic target in human malignancies. OBJECTIVE/METHODS: We evaluated the sensitivity of thyroid carcinoma cell lines (two papillary, one follicular, two anaplastic, three medullary) in vitro to BH3I-1 and BH3I-2', two cell-permeable inhibitors of the Bcl-2 homology (BH)-3 domain-mediated interaction between proapoptotic and antiapoptotic Bcl-2 family members. The thyroid carcinoma cell line FRO was stably transfected with cDNA for Bcl-2 or constitutively active Akt and evaluated for sensitivity to BH3-domain inhibition. RESULTS: BH3-domain inhibition disrupted the mitochondrial membrane potential in thyroid carcinoma cells, induced caspase-dependent apoptosis, and potently sensitized them to sublethal concentrations of doxorubicin and the proteasome inhibitor bortezomib (Velcade). Overexpression of constitutively active Akt suppressed BH3I-1-induced cell death. Bcl-2-overexpressing FRO cells were more resistant to conventional chemotherapeutic agents (such as doxorubicin) but significantly more sensitive to BH3I-1 than control cells and were found to overexpress caspase-9, caspase-8, Bmf, Bok, and Bik transcripts and express less A1, BRaf, and FLIP transcripts. CONCLUSIONS: Bcl-2 expression protects thyroid carcinomas against chemotherapy-induced apoptosis. Nevertheless, overexpression of Bcl-2 may result in "oncogene addiction" of the cancer cell, which can be exploited by using BH3-domain inhibitors alone or in combination with other agents, including conventional chemotherapeutics (such as doxorubicin) or novel targeted therapies (such as the proteasome inhibitor bortezomib), for the treatment of aggressive thyroid cancer, including the medullary and anaplastic types.


Subject(s)
Carcinoma, Medullary/genetics , Carcinoma/genetics , Genes, bcl-2/genetics , Thyroid Neoplasms/genetics , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents/pharmacology , BH3 Interacting Domain Death Agonist Protein/genetics , Blotting, Western , Boronic Acids/pharmacology , Bortezomib , Cell Line, Tumor , Colorimetry , Doxorubicin/pharmacology , Humans , Membrane Potentials/physiology , Oncogene Protein v-akt/genetics , Protease Inhibitors/pharmacology , Pyrazines/pharmacology , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Tetrazolium Salts , Thiazoles , Transcription, Genetic
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