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Burger, K. ; Mühl, B. ; Harasim, T. ; Rohrmoser, M. ; Malamoussi, A. ; Orban, M. ; Kellner, M. ; Gruber-Eber, A. ; Kremmer, E. ; Hölzel, M. ; Eick, D.

Chemotherapeutic drugs inhibit ribosome biogenesis at various levels.

J. Biol. Chem. 285, 12416-12425 (2010)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Drugs for cancer therapy belong to different categories of chemical substances. The cellular targets for the therapeutic efficacy are often not unambiguously identified. Here, we describe the process of ribosome biogenesis as a target of a large variety of chemotherapeutic drugs. We determined the inhibitory concentration of 36 chemotherapeutic drugs for transcription and processing of ribosomal RNA by in vivo labeling experiments. Inhibitory drug concentrations were correlated to the loss of nucleolar integrity. The synergism of drugs inhibiting ribosomal RNA synthesis at different levels was studied. Drugs inhibited ribosomal RNA synthesis either at the level of (i) rRNA transcription (e.g. oxaliplatin, doxorubicin, mitoxantrone, methotrexate), (ii) early rRNA processing (e.g. camptothecin, flavopiridol, roscovitine), or (iii) late rRNA processing (e.g. 5-fluorouracil, MG-132, homoharringtonine). Blockage of rRNA transcription or early rRNA processing steps caused nucleolar disintegration, whereas blockage of late rRNA processing steps left the nucleolus intact. Flavopiridol and 5-fluorouracil showed a strong synergism for inhibition of rRNA processing. We conclude that inhibition of ribosome biogenesis by chemotherapeutic drugs potentially may contribute to the efficacy of therapeutic regimens.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter U2 SNRNA; 5-Fluorouracil; Toxicity; Protein-interaction; Cell-proliferation; Pebow-complex; P53 Pathway; Transcription; Yeast; Disruption; Nucleolus
Sprache englisch
Veröffentlichungsjahr 2010
HGF-Berichtsjahr 2010
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 285, Heft: 16, Seiten: 12416-12425 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
Institute of Molecular Immunology (IMI)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501490-001
G-501700-003
PubMed ID 20159984
DOI 10.1074/jbc.M109.074211
Scopus ID 77951248778
Erfassungsdatum 2010-11-16
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