Jun 8, 2013

Mechanism of mitotic arrest induced by dolastatin 15 involves loss of tension across kinetochore pairs

Molecular and Cellular Biochemistry
Manu Lopus


Dolastatin 15 (DL15) is a potent, tubulin-targeted, vinca-site binding, anticancer agent that induces mitotic arrest and inhibit cell proliferation in a variety of cell types. Several analogs of DL15, including LU 103793 and tasidotin, have been progressed to clinical trials for different types of cancer. DL15 has been known to interfere with cellular microtubules and purified tubulin in vitro. However, the molecular mechanism with which the peptide arrests cells in mitosis is poorly understood. This study reports a possible antimitotic mechanism of action of DL15. DL15 inhibited HeLa cell proliferation in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 2.8 ± 0.3 nM, induced mitotic arrest, disrupted cellular microtubules near its IC50 for cell proliferation, and inhibited the re-polymerization of cellular microtubules. By staining the centrosomes of DL15-treated cells with anti-γ tubulin antibodies, the study found a significant reduction in interpolar distances in mitotic HeLa cells, indicating a disruption in the normal assembly dynamics of the microtubules. The study further found that DL15 induced a loss of tension across the kinetochore pairs as indicated by a reduction in interkine...Continue Reading

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Mentioned in this Paper

BUB1B gene
TUBE1 gene
Dolastatin Compound
Depsipeptides, Cyclic
LU 103793
Cell Proliferation

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