title: Effects of novel taxanes SB-T-1213 and IDN5109 on tubulin polymerization and mitosis.
abstract: SB-T-1213 and IDN5109 are semisynthetic, orally available taxanes that are up to 400-fold more active than paclitaxel against drug-resistant cells. IDN5109 is in clinical trials. We investigated the primary target for SB-T-1213 and IDN5109 and whether the compounds interact with microtubules differently than paclitaxel. Unlike paclitaxel, at 1-10 microM both novel taxanes initiate microtubule polymerization in vitro with no lag. They enhance polymerization equally or more potently than paclitaxel. SB-T-1213 induces unusual microtubules with attached extra protofilaments or open sheets, and IDN5109 induces large protofilamentous sheets. Both inhibit HeLa cell proliferation, block mitosis at the metaphase/anaphase transition, bundle microtubules at high drug concentrations, and induce abnormal metaphase spindles and apoptosis. They target microtubules but alter their polymerization and structure differently than paclitaxel. These differences may play a role in their enhanced cytotoxicity and efficacy.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and The Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA. jordan@lifesci.ucsb.edu
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Jordan
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.forename: Francisco
authors.initials: F
authors.lastname: Rosas
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Distefano
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Cristiano
authors.initials: C
authors.lastname: Ferlini
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008854:Microscopy, Electron; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008938:Mitosis / Q000187:drug effects*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D043823:Taxoids; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; C101718:SB T-1213; D043823:Taxoids; D014404:Tubulin; C404743:IDN 5109; D017239:Paclitaxel