Microtubule binding and disruption and induction of premature senescence by disorazole C(1).

نویسندگان

  • Marni Brisson Tierno
  • Carolyn A Kitchens
  • Bethany Petrik
  • Thomas H Graham
  • Peter Wipf
  • Fengfeng L Xu
  • William S Saunders
  • Brianne S Raccor
  • Raghavan Balachandran
  • Billy W Day
  • Jane R Stout
  • Claire E Walczak
  • Alexander P Ducruet
  • Celeste E Reese
  • John S Lazo
چکیده

Disorazoles comprise a family of 29 macrocyclic polyketides isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. The major fermentation product, disorazole A(1), was found previously to irreversibly bind to tubulin and to have potent cytotoxic activity against tumor cells, possibly because of its highly electrophilic epoxide moiety. To test this hypothesis, we synthesized the epoxide-free disorazole C(1) and found it retained potent antiproliferative activity against tumor cells, causing prominent G(2)/M phase arrest and inhibition of in vitro tubulin polymerization. Furthermore, disorazole C(1) produced disorganized microtubules at interphase, misaligned chromosomes during mitosis, apoptosis, and premature senescence in the surviving cell populations. Using a tubulin polymerization assay, we found disorazole C(1) inhibited purified bovine tubulin polymerization, with an IC(50) of 11.8 +/- 0.4 microM, and inhibited [3H]vinblastine binding noncompetitively, with a K(i) of 4.5 +/- 0.6 microM. We also found noncompetitive inhibition of [3H]dolastatin 10 binding by disorazole C(1), with a K(i) of 10.6 +/- 1.5 microM, indicating that disorazole C(1) bound tubulin uniquely among known antimitotic agents. Disorazole C(1) could be a valuable chemical probe for studying the process of mitotic spindle disruption and its relationship to premature senescence.

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منابع مشابه

Microtubule Binding and Disruption and Induction of Premature Senescence by Disorazole C1 □S

Disorazoles comprise a family of 29 macrocyclic polyketides isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. The major fermentation product, disorazole A1, was found previously to irreversibly bind to tubulin and to have potent cytotoxic activity against tumor cells, possibly because of its highly electrophilic epoxide moiety. To test this hypothesis, we synthesiz...

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Identifying a resistance determinant for the antimitotic natural products disorazole C1 and A1.

Disorazoles are macrocyclic polyketides first isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. Both the major fermentation product disorazole A(1) and its much rarer companion disorazole C(1) exhibit potent cytotoxic activity against many human tumor cells. Furthermore, the disorazoles appear to bind tubulin uniquely among known antimitotic agents, promoting apopt...

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Identifying a Resistance Determinant for the Antimitotic Natural Products Disorazole C1 and A1 □S

Disorazoles are macrocyclic polyketides first isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. Both the major fermentation product disorazole A1 and its much rarer companion disorazole C1 exhibit potent cytotoxic activity against many human tumor cells. Furthermore, the disorazoles appear to bind tubulin uniquely among known antimitotic agents, promoting apoptosis...

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Bis-cyclopropane analog of disorazole C1 is a microtubule-destabilizing agent active in ABCB1-overexpressing human colon cancer cells.

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Mitotic slippage in non-cancer cells induced by a microtubule disruptor, disorazole C1

BACKGROUND Disorazoles are polyene macrodiolides isolated from a myxobacterium fermentation broth. Disorazole C1 was newly synthesized and found to depolymerize microtubules and cause mitotic arrest. Here we examined the cellular responses to disorazole C1 in both non-cancer and cancer cells and compared our results to vinblastine and taxol. RESULTS In non-cancer cells, disorazole C1 induced ...

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عنوان ژورنال:
  • The Journal of pharmacology and experimental therapeutics

دوره 328 3  شماره 

صفحات  -

تاریخ انتشار 2009