title: Small molecule growth inhibitors of human oncogenic gammaherpesvirus infected B-cells.
abstract: Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are two human gammaherpesviruses associated with a broad spectrum of B-cell lymphomas, most acutely in immuno-compromised populations. However, there are no drugs which specifically target KSHV or EBV-associated lymphomas. To identify small molecules which selectively inhibit the growth of EBV or KSHV-associated B-cell lines, we performed a fluorescence based high-throughput screen on multiple stable GFP expressing virus-infected or uninfected B-cell lines. We identified 40 initial compounds with selective growth inhibition and subsequently determined the 50% growth inhibitory concentrations (GI50) for each drug. We further examined compounds with higher specificity to explore the underlying molecular mechanisms using transcription factor analysis, as well as a shRNA based knockdown strategy. Our data identified ten compounds with relatively high efficacy for growth inhibition. Two novel small molecules, NSC#10010 and NSC#65381 were potent growth inhibitors for gammaherpesvirus-associated B-lymphomas through activation of both the NF-κB and c-Myc-mediated signaling pathways. These drugs can serve as potential lead compounds to expand the current therapeutic window against EBV or KSHV-associated human B-cell malignancies.
authors.affiliation: Department of Microbiology and Tumor Virology Program of the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, PA, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Dzeng
authors.affiliation: Department of Microbiology and Tumor Virology Program of the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, PA, USA.
authors.forename: Hem Chandra
authors.initials: HC
authors.lastname: Jha
authors.affiliation: Department of Microbiology and Tumor Virology Program of the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, PA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Microbiology and Tumor Virology Program of the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, PA, USA.
authors.forename: Abhik
authors.initials: A
authors.lastname: Saha
authors.affiliation: Department of Microbiology and Tumor Virology Program of the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, PA, USA.
authors.forename: Sagarika
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Microbiology and Tumor Virology Program of the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, PA, USA. Electronic address: erle@upenn.edu.
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; C489427:MYC protein, human; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc
keywords: EBV; High throughput drug screening; KSHV; Lymphoma