Tubulin assembly, taxoid site binding, and cellular effects of the microtubule-stabilizing agent dictyostatin.
(-)-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 beta-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.
Madiraju
Charitha
C
Department of Pharmaceutical Sciences, Chemistry, and Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Edler
Michael C
MC
Hamel
Ernest
E
Raccor
Brianne S
BS
Balachandran
Raghavan
R
Zhu
Guangyu
G
Giuliano
Kenneth A
KA
Vogt
Andreas
A
Shin
Youseung
Y
Fournier
Jean-Hugues
JH
Fukui
Yoshikazu
Y
Brückner
Arndt M
AM
Curran
Dennis P
DP
Day
Billy W
BW
D000473:Alkanes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002219:Carbamates / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects* / Q000648:ultrastructure; D017239:Paclitaxel / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism*
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D018942:Macrolides; D011753:Pyrones; D014404:Tubulin; C470814:dictyostatin; C071229:discodermolide; D017239:Paclitaxel