title: The Interference of Selected Cytotoxic Alkaloids with the Cytoskeleton: An Insight into Their Modes of Action.
abstract: Alkaloids, the largest group among the nitrogen-containing secondary metabolites of plants, usually interact with several molecular targets. In this study, we provide evidence that six cytotoxic alkaloids (sanguinarine, chelerythrine, chelidonine, noscapine, protopine, homoharringtonine), which are known to affect neuroreceptors, protein biosynthesis and nucleic acids, also interact with the cellular cytoskeleton, such as microtubules and actin filaments, as well. Sanguinarine, chelerythrine and chelidonine depolymerized the microtubule network in living cancer cells (Hela cells and human osteosarcoma U2OS cells) and inhibited tubulin polymerization in vitro with IC50 values of 48.41 ± 3.73, 206.39 ± 4.20 and 34.51 ± 9.47 μM, respectively. However, sanguinarine and chelerythrine did not arrest the cell cycle while 2.5 μM chelidonine arrested the cell cycle in the G₂/M phase with 88.27% ± 0.99% of the cells in this phase. Noscapine and protopine apparently affected microtubule structures in living cells without affecting tubulin polymerization in vitro, which led to cell cycle arrest in the G2/M phase, promoting this cell population to 73.42% ± 8.31% and 54.35% ± 11.26% at a concentration of 80 μM and 250.9 μM, respectively. Homoharringtonine did not show any effects on microtubules and cell cycle, while the known microtubule-stabilizing agent paclitaxel was found to inhibit tubulin polymerization in the presence of MAPs in vitro with an IC50 value of 38.19 ± 3.33 μM. Concerning actin filaments, sanguinarine, chelerythrine and chelidonine exhibited a certain effect on the cellular actin filament network by reducing the mass of actin filaments. The interactions of these cytotoxic alkaloids with microtubules and actin filaments present new insights into their molecular modes of action.
authors.affiliation: Department of Biology, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364, D-69120 Heidelberg, Germany. wxjsz@hotmail.com.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biology, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364, D-69120 Heidelberg, Germany. mine_tanaka@hotmail.com.
authors.forename: Mine
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Biology, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364, D-69120 Heidelberg, Germany. Krstin@uni-heidelberg.de.
authors.forename: Sonja
authors.initials: S
authors.lastname: Krstin
authors.affiliation: Department of Biology, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364, D-69120 Heidelberg, Germany. hspeixoto1@gmail.com.
authors.forename: Herbenya Silva
authors.initials: HS
authors.lastname: Peixoto
authors.affiliation: Department of Biology, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364, D-69120 Heidelberg, Germany. wink@uni-heidelberg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Wink
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000199:Actins; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin
keywords: actin filaments; alkaloids; chelerythrine; chelidonine; homoharringtonine; microtubules; noscapine; paclitaxel; protopine; sanguinarine