Tubulin assembly, taxoid site binding, and cellular effects of the microtubule-stabilizing agent dictyostatin

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

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Author(s)

  • Charitha Madiraju
  • Michael C. Edler
  • Ernest Hamel
  • Brianne S. Raccor
  • Raghavan Balachandran
  • Kenneth A. Giuliano
  • Andreas Vogt
  • Youseung Shin
  • Jean-Hugues Fournier
  • Yoshikazu Fukui
  • Arndt M. Brückner
  • Dennis P. Curran
  • Billy W. Day

Detail(s)

Original languageEnglish
Pages (from-to)15053-15063
Journal / PublicationBiochemistry
Volume44
Issue number45
Publication statusPublished - 15 Nov 2005
Externally publishedYes

Abstract

(-)-Dictyostatin is a sponge-derived, 22-member macrolactone natural product shown to cause cells to accumulate in the G2/M phase of the cell cycle, with changes in intracellular microtubules analogous to those observed with paclitaxel treatment. Dictyostatin also induces assembly of purified tubulin more rapidly than does paclitaxel, and nearly as vigorously as does dictyostatin's close structural congener, (+)-discodermolide (Isbrucker et al, (2003), Biochem. Pharmacol 65, 75-82). We used synthetic (-)-dictyostatin to study its biochemical and cytological activities in greater detail. The antiproliferative activity of dictyostatin did not differ greatly from that of paclitaxel or discodermolide. Like discodermolide, dictyostatin retained antiproliferative activity against human ovarian carcinoma cells resistant to paclitaxel due to β-tubulin mutations and caused conversion of cellular soluble tubulin pools to microtubules. Detailed comparison of the abilities of dictyostatin and discodermolide to induce tubulin assembly demonstrated that the compounds had similar potencies. Dictyostatin inhibited the binding of radiolabeled discodermolide to microtubules more potently than any other compound examined, and dictyostatin and discodermolide had equivalent activity as inhibitors of the binding of both radiolabeled epothilone B and paclitaxel to microtubules. These results are consistent with the idea that the macrocyclic structure of dictyostatin represents the template for the bioactive conformation of discodermolide. © 2005 American Chemical Society.

Citation Format(s)

Tubulin assembly, taxoid site binding, and cellular effects of the microtubule-stabilizing agent dictyostatin. / Madiraju, Charitha; Edler, Michael C.; Hamel, Ernest; Raccor, Brianne S.; Balachandran, Raghavan; Zhu, Guangyu; Giuliano, Kenneth A.; Vogt, Andreas; Shin, Youseung; Fournier, Jean-Hugues; Fukui, Yoshikazu; Brückner, Arndt M.; Curran, Dennis P.; Day, Billy W.

In: Biochemistry, Vol. 44, No. 45, 15.11.2005, p. 15053-15063.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal