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Probing the role of the potent microtubule disrupting agent disorazole C 1 in premature cellular senescence induction
Author(s) -
Kitchens Carolyn A,
Tierno Marni Brisson,
Petrik Bethany,
Graham Thomas H,
Wipf Peter,
Raccor Brianne S,
Balachandran Raghavan,
Day Billy W,
Reese Celeste E,
Lazo John S
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.642.1
Subject(s) - tubulin , senescence , microbiology and biotechnology , microtubule , intracellular , cell growth , biology , vinblastine , extracellular , cell culture , cancer cell , cell , biochemistry , cancer , genetics , chemotherapy
Cellular senescence is a permanent state of cell cycle arrest that prevents cell proliferation but allows the cells to be metabolically active. Premature cellular senescence is stimulated by a variety of extracellular and intracellular stimuli including oxidative damage, supraphysiological mitogenic signaling, transforming growth factor‐β, retinoids, oncogenes, DNA damage and some cancer chemotherapeutic agents. Disorazoles are macrocyclic polyketides isolated from the fermentation broth of the myxobacterium Sorangium cellulosum that are potent inhibitors of tubulin polymerization. We synthesized disorazole C 1 and found it inhibited in vitro tubulin polymerization and competed with vinblastine and dolastatin 10 for binding to purified tubulin. Treatment with disorazole C 1 caused profound inhibition of cell proliferation in a wide variety of cancer cell lines. In cells surviving 7 days of treatment, disorazole C 1 induced a senescent phenotype at concentrations equal to or below the IC 50 for growth inhibition. Additionally, we observed that a variety of other inhibitors of tubulin polymerization also induced a senescent phenotype indicating that, like other mechanisms of cellular stress, microtubule disruption can induce premature cellular senescence. This research was funded in part by USPH grant CA78039.