Improved cellular pharmacokinetics and pharmacodynamics underlie the wide anticancer activity of sagopilone

Jens Hoffmann, Ilio Vitale, Bernd Buchmann, Lorenzo Galluzzi, Wolfgang Schwede, Laura Senovilla, Werner Skuballa, Sonia Vivet, Rosemarie B. Lichtner, José M. Vicencio, Theocharis Panaretakis, Gerhard Siemeister, Hermann Lage, Lisa Nanty, Stefanie Hammer, Kevin Mittelstaedt, Sebastian Winsel, Julia Eschenbrenner, Maria Castedo, Carine DemarcheUlrich Klar, Guido Kroemer

Research output: Contribution to journalArticle

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-XL, 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.

Original languageEnglish
Pages (from-to)5301-5308
Number of pages8
JournalCancer Research
Volume68
Issue number13
DOIs
Publication statusPublished - Jul 1 2008

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Hoffmann, J., Vitale, I., Buchmann, B., Galluzzi, L., Schwede, W., Senovilla, L., Skuballa, W., Vivet, S., Lichtner, R. B., Vicencio, J. M., Panaretakis, T., Siemeister, G., Lage, H., Nanty, L., Hammer, S., Mittelstaedt, K., Winsel, S., Eschenbrenner, J., Castedo, M., ... Kroemer, G. (2008). Improved cellular pharmacokinetics and pharmacodynamics underlie the wide anticancer activity of sagopilone. Cancer Research, 68(13), 5301-5308. https://doi.org/10.1158/0008-5472.CAN-08-0237