title: Induction of HEXIM1 activities by HMBA derivative 4a1: Functional consequences and mechanism.
abstract: We have been studying the role of Hexamethylene bisacetamide (HMBA) Induced Protein 1 (HEXIM1) as a tumor suppressor whose expression is decreased in tamoxifen resistant and metastatic breast cancer. HMBA was considered the most potent and specific inducer for HMBA inducible protein 1 (HEXIM1) prior to our studies. Moreover, the ability of HMBA to induce differentiation is advantageous for its therapeutic use when compared to cytotoxic agents. However, HMBA induced HEXIM1 expression required at mM concentrations and induced dose limiting toxicity, thrombocytopenia. Thus we structurally optimized HMBA and identified a more potent inducer of HEXIM1 expression, 4a1. The studies reported herein tested the ability of 4a1 to induce HEXIM1 activities using a combination of biochemical, cell phenotypic, and in vivo assays. 4a1 induced breast cell differentiation, including the stem cell fraction in triple negative breast cancer cells. Clinically relevant HEXIM1 activities that are also induced by 4a1 include enhancement of the inhibitory effects of tamoxifen and inhibition of breast tumor metastasis. We also provide mechanistic basis for the phenotypic effects of 4a1. Our results support the potential of an unsymmetrical HMBA derivative, such as 4a1, as lead compound for further drug development.
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Wannarasmi
authors.initials: W
authors.lastname: Ketchart
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: I-Ju
authors.initials: IJ
authors.lastname: Yeh
authors.affiliation: Department of Radiology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Haoyan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Praveena S
authors.initials: PS
authors.lastname: Thiagarajan
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Lathia
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Ofer
authors.initials: O
authors.lastname: Reizes
authors.affiliation: Department of Radiology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Agata
authors.initials: A
authors.lastname: Exner
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Su
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Electronic address: monica.montano@case.edu.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Montano
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D015394:Molecular Structure; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000081:Acetamides; D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D044482:Benzeneacetamides; C476123:HEXIM1 protein, human; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D013629:Tamoxifen; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; C014026:hexamethylene bisacetamide
keywords: Antiestrogens; Breast cells; Differentiation; HEXIM1; HMBA; Metastasis