title: Actin-binding doliculide causes premature senescence in p53 wild type cells.
abstract: Addressing the actin cytoskeleton as future anticancer target can be an innovative chemotherapeutic approach to combat malignancies. Doliculide is a potent stabilizer of actin filaments and can be used as tool and therapeutic lead in cancer research. Though a variety of molecules are known to bind to actin and lead to either its over- or depolymerization little is known about the pharmacological consequences of these effects within the cancer cell. In this work we used p53 wild-type cells to dissect the reaction of these cells towards subtoxic doses of doliculide. We could show that doliculide leads to a transient change in actin cytoskeleton dynamics that are reversible. The cells react towards the treatment with the induction of premature senescence, an established anti-cancer mechanism, in concentrations that are not cytotoxic. Furthermore, we investigated the signaling pathways that are involved in the induction and maintenance of senescence by a pathway directed mRNA PCR-array. This analysis revealed that under doliculide treatment up to 13% of senescence related genes are altered. Taken together, our data provide evidence for an antitumoral potential of actin binding agents in p53 wild type cells and brings the strategy of targeting the actin cytoskeleton closer to clinical application.
authors.affiliation: Department of Pharmacy-Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: florian.foerster@cup.uni-muenchen.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Foerster
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.affiliation: Department of Pharmacy-Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D047630:Depsipeptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D016133:Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D047630:Depsipeptides; D016159:Tumor Suppressor Protein p53; C424144:doliculide
keywords: Actin; Doliculide; RT(2) Profiler™ PCR Array; Senescence; p53