The microtubule stabilizing agent discodermolide is a potent inducer of accelerated cell senescence.
Discodermolide is a microtubule stabilizing agent that suppresses dynamic instability and blocks cells in mitosis. Selection of A549 nonsmall cell lung carcinoma cells with increasing concentrations of discodermolide yielded a clone that proliferated in 8 nM. When these cells were exposed to any concentration greater than 8 nM, replication ceased and the cells developed a flattened, enlarged, granular morphology. Accelerated senescence was demonstrated by a functional beta-galactosidase activity at pH 6. When parental A549 cells were treated with IC50-concentrations of doxorubicin, Taxol or discodermolide, the latter two drugs quickly produced aberrant mitosis. However, discodermolide, but not Taxol, also produced a large increase in senescence-associated beta-galactosidase activity and altered levels of known senescence markers. Although some of these differences between Taxol and discodermolide were dose dependent, only discodermolide produced a doxorubicin-like induction of a senescence phenotype, including a senescence-associated beta-galactosidase activity, up-regulation of PAI-1 and p66Shc, and a strong, sustained, Erk1/2 activation. This research provides insights into the mechanism of action of discodermolide and provides the first demonstration of a microtubule stabilizing agent that inhibits tumor cell growth with a powerful induction of accelerated senescence.
Klein
Laura E
LE
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA.
Freeze
B Scott
BS
Smith
Amos B
AB
Horwitz
Susan Band
SB
D000473:Alkanes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000494:pharmacology*; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008938:Mitosis; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D011753:Pyrones / Q000494:pharmacology*; D015398:Signal Transduction; D013997:Time Factors
D000473:Alkanes; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002219:Carbamates; D007783:Lactones; D011753:Pyrones; C071229:discodermolide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001973:Bromodeoxyuridine; D017239:Paclitaxel