title: 9-Benzylidene-naphtho[2,3-b]thiophen-4-ones and benzylidene-9(10H)-anthracenones as novel tubulin interacting agents with high apoptosis-inducing activity.
abstract: Tubulin-binding 9-benzylidene-naphtho[2,3-b]thiophen-4-ones 1a and 1b and benzylidene-9(10H)-anthracenone 2 were evaluated for their ability to induce cell death. We examined the effect of the molecules on cell cycle progression, organization of microtubule networks, and apoptosis induction. As determined by flow cytometry, cancer cells were predominantly arrested in metaphase with 4N DNA before cell death occurred. By using indirect immunofluorescence techniques we visualized microtubule depolymerization recognizable by short microtubule fragments scattered around the nucleus. The incubation with 1a and 2 resulted in chromatin condensation, nuclear fragmentation, and cell shrinkage, which are, among others, typical features of apoptotic cell death. Furthermore, time- and dose-dependent induction of apoptosis in SH-SY5Y cells was detected via cleavage of Ac-DEVD-AMC, a fluorigenic substrate for caspase-3. We observed a lower apoptotic activity in neuroblastoma cells overexpressing Bcl-xL, suggesting activation of the mitochondrial apoptosis pathway. Western blot analysis demonstrated that caspase-3, an apoptosis mediator, was activated in a time-dependent manner after exposure of SH-SY5Y cells to drugs 1a and 2. Taken together, the agents investigated in the present study display strong apoptosis-inducing activity and therefore show promise for the development of novel chemotherapeutics.
authors: Manitoba Institute of Cell Biology, CancerCare Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, Canada.
authors: Anne
authors: A
authors: Zuse
authors: Helge
authors: H
authors: Prinz
authors: Klaus
authors: K
authors: Müller
authors: Peter
authors: P
authors: Schmidt
authors: Eckhard G
authors: EG
authors: Günther
authors: Frank
authors: F
authors: Schweizer
authors: Jochen H M
authors: JH
authors: Prehn
authors: Marek
authors: M
authors: Los
mesh_terms: D000873:Anthracenes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C476444:10-((3-hydroxy-4-methoxybenzylidene))-9(10H)-anthracenone; D000873:Anthracenes; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D002843:Chromatin; D009281:Naphthalenes; D019253:Proto-Oncogene Proteins c-bcl-2; D013876:Thiophenes; D050257:Tubulin Modulators; D053148:Caspase 3