title: Improved cellular pharmacokinetics and pharmacodynamics underlie the wide anticancer activity of sagopilone.
abstract: Sagopilone (ZK-EPO) is the first fully synthetic epothilone undergoing clinical trials for the treatment of human tumors. Here, we investigate the cellular pathways by which sagopilone blocks tumor cell proliferation and compare the intracellular pharmacokinetics and the in vivo pharmacodynamics of sagopilone with other microtubule-stabilizing (or tubulin-polymerizing) agents. Cellular uptake and fractionation/localization studies revealed that sagopilone enters cells more efficiently, associates more tightly with the cytoskeleton, and polymerizes tubulin more potently than paclitaxel. Moreover, in contrast to paclitaxel and other epothilones [such as the natural product epothilone B (patupilone) or its partially synthetic analogue ixabepilone], sagopilone is not a substrate of the P-glycoprotein efflux pumps. Microtubule stabilization by sagopilone caused mitotic arrest, followed by transient multinucleation and activation of the mitochondrial apoptotic pathway. Profiling of the proapoptotic signal transduction pathway induced by sagopilone with a panel of small interfering RNAs revealed that sagopilone acts similarly to paclitaxel. In HCT 116 colon carcinoma cells, sagopilone-induced apoptosis was partly antagonized by the knockdown of proapoptotic members of the Bcl-2 family, including Bax, Bak, and Puma, whereas knockdown of Bcl-2, Bcl-X(L), or Chk1 sensitized cells to sagopilone-induced cell death. Related to its improved subcellular pharmacokinetics, however, sagopilone is more cytotoxic than other epothilones in a large panel of human cancer cell lines in vitro and in vivo. In particular, sagopilone is highly effective in reducing the growth of paclitaxel-resistant cancer cells. These results underline the processes behind the therapeutic efficacy of sagopilone, which is now evaluated in a broad phase II program.
authors.affiliation: Bayer Schering Pharma AG, TRG Oncology, Müllerstrasse 72-178, G-13342 Berlin, Germany. jens.hoffmann@bayerhealthcare.com
authors.forename: Jens
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.forename: Bernd
authors.initials: B
authors.lastname: Buchmann
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schwede
authors.forename: Laura
authors.initials: L
authors.lastname: Senovilla
authors.forename: Werner
authors.initials: W
authors.lastname: Skuballa
authors.forename: Sonia
authors.initials: S
authors.lastname: Vivet
authors.forename: Rosemarie B
authors.initials: RB
authors.lastname: Lichtner
authors.forename: José M
authors.initials: JM
authors.lastname: Vicencio
authors.forename: Theocharis
authors.initials: T
authors.lastname: Panaretakis
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
authors.forename: Hermann
authors.initials: H
authors.lastname: Lage
authors.forename: Lisa
authors.initials: L
authors.lastname: Nanty
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hammer
authors.forename: Kevin
authors.initials: K
authors.lastname: Mittelstaedt
authors.forename: Sebastian
authors.initials: S
authors.lastname: Winsel
authors.forename: Julia
authors.initials: J
authors.lastname: Eschenbrenner
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Carine
authors.initials: C
authors.lastname: Demarche
authors.forename: Ulrich
authors.initials: U
authors.lastname: Klar
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000493:pharmacokinetics*; D034261:Epothilones / Q000493:pharmacokinetics*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D014018:Tissue Distribution; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D034261:Epothilones; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; C530494:sagopilone