A Synthetic Dolastatin 10 Analogue Suppresses Microtubule Dynamics, Inhibits Cell Proliferation, and Induces Apoptotic Cell Death
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Title |
A Synthetic Dolastatin 10 Analogue Suppresses Microtubule Dynamics, Inhibits Cell Proliferation, and Induces Apoptotic Cell Death
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Creator |
GAJULA, PK
ASTHANA, J PANDA, D CHAKRABORTY, TK |
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Subject |
SUGAR AMINO-ACIDS
TUBULIN BINDING CANCER-CELLS COMBINATORIAL SYNTHESIS KINETIC STABILIZATION QUANTITATIVE-ANALYSIS ANTICANCER DRUGS MITOTIC ARREST BETA-TUBULIN PHASE-I |
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Description |
We have synthesized eight analogues (D1-D8) of dolastatin 10 containing several unique amino acid subunits. Of these agents, D5 was found to be most effective in inhibiting both He La cell proliferation and microtubule assembly in vitro. At low nanomolar concentrations, 135 inhibited the proliferation of several types of cancer cells in culture. D5 bound to tubulin with a dissociation constant of 29.4 +/- 6 mu M. D5 depolymerized microtubules in cultured cells and produced mulitpolar spindles. At its half-maximal inhibitory concentration (15 nM), DS strongly suppressed the dynamics of individual microtubules in live MCF-7 cells. DS increased the accumulation of checkpoint proteins BubR1 and Mad2 at the kinetochoric region and caused G2/M block in these cells. The blocked cells underwent apoptosis with the activation of Jun N-terminal kinase. The results suggested that DS exerts its antiproliferative action by dampening microtubule dynamics.
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Publisher |
AMER CHEMICAL SOC
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Date |
2014-10-16T13:56:44Z
2014-10-16T13:56:44Z 2013 |
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Type |
Article
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Identifier |
JOURNAL OF MEDICINAL CHEMISTRY, 56(6)2235-2245
0022-2623 1520-4804 http://dx.doi.org/10.1021/jm3009629 http://dspace.library.iitb.ac.in/jspui/handle/100/15722 |
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Language |
en
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