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1.
Mol Cancer Ther ; 14(10): 2167-74, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26253517

ABSTRACT

The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers, such as multiple myeloma. In this study, we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in downregulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need.


Subject(s)
Antineoplastic Agents/pharmacology , Azepines/pharmacology , Basic Helix-Loop-Helix Transcription Factors/genetics , Lung Neoplasms/metabolism , Nuclear Proteins/metabolism , Small Cell Lung Carcinoma/metabolism , Transcription Factors/metabolism , Triazoles/pharmacology , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Cycle Proteins , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm/genetics , Drug Screening Assays, Antitumor , Enhancer Elements, Genetic , Gene Expression , Gene Expression Regulation, Neoplastic/drug effects , Humans , Inhibitory Concentration 50 , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Protein Binding , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/genetics , Transcriptome/drug effects
2.
Cancer Chemother Pharmacol ; 63(2): 201-12, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18350296

ABSTRACT

PURPOSE: Ixabepilone, a semisynthetic analog of natural epothilone B, was developed for use in cancer treatment. This study extends previous findings regarding the efficacy of ixabepilone and its low susceptibility to tumor resistance mechanisms and describes the pharmacokinetics of this new antineoplastic agent. METHODS: The cytotoxicity of ixabepilone was assessed in vitro in breast, lung, and colon tumor cell lines and in vivo in human xenografts in mice. Antitumor activities of ixabepilone and taxanes were compared in multidrug-resistant models in vivo. Differential drug uptake of ixabepilone and paclitaxel was assessed in a P-glycoprotein (P-gp)-resistant colon cancer model in vitro. The pharmacokinetic profile of ixabepilone was established in mice and humans. RESULTS: Ixabepilone demonstrated potent cytotoxicity in a broad range of human cancer cell lines in vitro and in a wide range of xenografts in vivo. Ixabepilone was *3-fold more potent than docetaxel in the paclitaxel-resistant Pat-21 xenograft model (resistant due to overexpression of betaIII-tubulin and a lack of betaII-tubulin). Ixabepilone activity against P-gp-overexpressing breast and colon cancer was confirmed in in vivo models. Cellular uptake of ixabepilone, but not paclitaxel, was established in a P-gp-overexpressing model. The pharmacokinetics of ixabepilone was characterized by rapid tissue distribution and extensive tissue binding. CONCLUSIONS: Cytotoxicity studies against a range of tumor types in vitro and in vivo demonstrate that ixabepilone has potent and broad-spectrum antineoplastic activity. This is accompanied by favorable pharmacokinetics. Ixabepilone has reduced susceptibility to resistance due to P-gp overexpression, tubulin mutations, and alterations in beta-tubulin isotype expression.


Subject(s)
Antineoplastic Agents , Epothilones , Neoplasms , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Area Under Curve , Cell Line, Tumor , Cell Survival/drug effects , Chromatography, High Pressure Liquid , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Epothilones/pharmacokinetics , Epothilones/pharmacology , Epothilones/therapeutic use , Female , Humans , Mass Spectrometry , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Nude , Mice, SCID , Neoplasm Transplantation , Neoplasms/drug therapy , Neoplasms/metabolism , Tubulin Modulators/pharmacokinetics , Tubulin Modulators/pharmacology , Tubulin Modulators/therapeutic use , Xenograft Model Antitumor Assays
3.
J Med Chem ; 47(27): 6658-61, 2004 Dec 30.
Article in English | MEDLINE | ID: mdl-15615512

ABSTRACT

A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Pyrimidines/pharmacology , Thiazoles/pharmacology , src-Family Kinases/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Animals , Dasatinib , Humans , K562 Cells , Mice , Proto-Oncogene Proteins c-abl/chemistry , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Thiazoles/pharmacokinetics , src-Family Kinases/chemistry
4.
J Nat Prod ; 65(2): 95-9, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11858737

ABSTRACT

Fractionation of a methanol extract of the leaves and twigs of Casearia sylvestris, as directed by activity against KB cell cytotoxicity, led to the isolation of three novel clerodane diterpenoids, casearvestrins A-C (1-3). The structures of 1-3 were deduced from one- and two-dimensional NMR experiments, including relative stereochemical assignments based on ROESY correlations and COSY coupling constants. All three compounds displayed promising bioactivity, both in cytotoxicity assays against a panel of tumor cell lines and in antifungal assays via the growth inhibition of Aspergillus niger in a disk diffusion assay.


Subject(s)
Antifungal Agents/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Diterpenes/isolation & purification , Magnoliopsida/chemistry , Plants, Medicinal/chemistry , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Aspergillus niger/drug effects , Colonic Neoplasms , Diterpenes/chemistry , Diterpenes/pharmacology , Drug Screening Assays, Antitumor , Ecuador , Female , Humans , Inhibitory Concentration 50 , KB Cells/drug effects , Lung Neoplasms , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Ovarian Neoplasms , Plant Leaves/chemistry , Plant Shoots/chemistry , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Spectroscopy, Fourier Transform Infrared , Tumor Cells, Cultured/drug effects
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