title: Pharmacological characterization of actin-binding (-)-doliculide.
abstract: Natural compounds offer a broad spectrum of potential drug candidates against human malignancies. Several cytostatic drugs, which are in clinical use for decades, derive directly from natural sources or are synthetically optimized derivatives of natural lead structures. An eukaryote target molecule to which many natural derived anti-cancer drugs bind to is the microtubule network. Of similar importance for the cell is the actin cytoskeleton, responsible for cell movements, migration of cells and cytokinesis. Nature provides also a broad range of compounds directed against actin as intracellular target, but none of these actin-targeting compounds has ever been brought to clinical trials. One reason why actin-binding compounds have not yet been considered for further clinical investigations is that little is known about their pharmacological properties in cancer cells. Herein, we focused on the closer characterization of doliculide, an actin binding natural compound of marine origin in the breast cancer cell lines MCF7 and MDA-MB-231. We used fluorescence-recovery-after-photobleaching (FRAP) analysis to determine doliculide's early effects on the actin cytoskeleton and rhodamin-phalloidin staining for long-term effects on the actin CSK. After validating the disruption of the actin network, we further investigated the functional effects of doliculide. Doliculide treatment leads to inhibition of proliferation and impairs the migratory potential. Finally, we could also show that doliculide leads to the induction of apoptosis in both cell lines. Our data for the first time provide a closer characterization of doliculide in breast cancer cells and propagate doliculide for further investigations as lead structure and potential therapeutic option as actin-targeting compound.
authors.affiliation: Department of Pharmacy-Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Foerster
authors.affiliation: Department of Pharmacy-Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Braig
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli-Straße 10, 8093 Zurich, Switzerland.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli-Straße 10, 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. Electronic address: Angelika.Vollmar@cup.uni-muenchen.de.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008968:Molecular Conformation; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000199:Actins; D000972:Antineoplastic Agents, Phytogenic; D047630:Depsipeptides; C424144:doliculide
keywords: Actin overpolymerization; Cell death; Doliculide