Suppression of Microtubule Dynamics by LY290181

Panda, Dulal; Singh, Jai Pal; Wilson, Leslie

doi:10.1074/jbc.272.12.7681

Cited by 68 publications

(49 citation statements)

References 36 publications

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“…ment around these amino acids in the folded protein. Agents that bind tubulin typically change the microenvironment and alter the fluorescent properties of the target protein (Peyrot et al, 1992;Panda et al, 1997;Ye et al, 1998). Measuring these fluorescent changes has become a standard method for determining the binding properties of tubulin ligands, including the classic compound colchicine (Peyrot et al, 1989;Andreu et al, 1991).…”

Section: Resultsmentioning

confidence: 99%

Development of a Novel Nitro-Derivative of Noscapine for the Potential Treatment of Drug-Resistant Ovarian Cancer and T-Cell Lymphoma

Aneja¹,

Vangapandu²,

Lopus³

et al. 2006

Mol Pharmacol

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We have shown previously that an antitussive plant alkaloid, noscapine, binds tubulin, displays anticancer activity, and has a safe pharmacological profile in humans. Structure-function analyses pointed to a proton at position-9 of the isoquinoline ring that can be modified without compromising tubulin binding activity. Thus, many noscapine analogs with different functional moieties at position-9 were synthesized. Those analogs that kill human cancer cells resistant to other antimicrotubule agents, vincas and taxanes, were screened. Here, we present one such analog, 9-nitro-noscapine (9-nitro-nos), which binds tubulin and induces apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine, and teniposide. 9-Nitro-nos treatment at doses as high as 100 M did not affect the cell cycle profile of normal human fibroblasts. This selectivity of 9-nitro-nos for cancer cells represents a unique edge over the other available antimitotics. 9-Nitro-nos perturbs the progression of cell cycle by mitotic arrest, followed by apoptotic cell death associated with increased caspase-3 activation and appearance of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. Thus, we conclude that 9-nitro-nos has great potential to be a novel therapeutic agent for ovarian and T-cell lymphoma cancers, even those that have become drug-resistant to currently available chemotherapeutic drugs.

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Section: Resultsmentioning

confidence: 99%

Development of a Novel Nitro-Derivative of Noscapine for the Potential Treatment of Drug-Resistant Ovarian Cancer and T-Cell Lymphoma

Aneja¹,

Vangapandu²,

Lopus³

et al. 2006

Mol Pharmacol

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“…Tubulin, like many other proteins, contains fluorescent amino acids like tryptophans and tyrosines and the intensity of the fluorescence emission is dependent upon the micro-environment around these amino acids in the folded protein. Agents that bind tubulin typically change the micro-environment and the fluorescent properties of the target protein [18,40,41]. Measuring these fluorescent changes has become a standard method for determining the binding properties of tubulin ligands including the classical compound colchicine [42].…”

Section: Halogenated Noscapine Analogs Have Higher Tubulinbinding Actmentioning

confidence: 99%

Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death

Aneja

Vangapandu

Lopus

et al. 2006

Biochemical Pharmacology

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115

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“…At or near steady state, both in vitro and in cells, microtubules spend a considerable fraction of time in an attenuated or pause phase (43)(44)(45)(46)(52)(53)(54)(55). EM strongly decreased the fraction of time the microtubules spent growing and increased the percentage of time that the microtubules spent in the attenuated state (Table 1).…”

Section: Inhibition Of Microtubule Polymerization By Emmentioning

confidence: 99%

“…For example, vinblastine and colchicine depolymerize spindle microtubules, whereas taxol increases spindle microtubule mass (38)(39)(40). However, we have recently found that while these and a number of other antimitotic drugs affect the microtubule polymer mass at relatively high drug concentrations, they all strongly suppress the dynamics of microtubules in the absence of significant effects on polymer mass at relatively low concentrations (40)(41)(42)(43)(44)(45)(46).…”

mentioning

confidence: 99%

Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: A possible mechanistic basis for its antitumor action

Panda

Miller

Islam

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The cellular targets for estramustine, an antitumor drug used in the treatment of hormone-refractory prostate cancer, are believed to be the spindle microtubules responsible for chromosome separation at mitosis. Estramustine only weakly inhibits polymerization of purified tubulin into microtubules by binding to tubulin (K d , Ϸ30 M) at a site distinct from the colchicine or the vinblastine binding sites. However, by video microscopy, we find that estramustine strongly stabilizes growing and shortening dynamics at plus ends of bovine brain microtubules devoid of microtubuleassociated proteins at concentrations substantially below those required to inhibit polymerization of the microtubules. Estramustine strongly reduced the rate and extent both of shortening and growing, increased the percentage of time the microtubules spent in an attenuated state, neither growing nor shortening detectably, and reduced the overall dynamicity of the microtubules. Significantly, the combined suppressive effects of vinblastine and estramustine on the rate and extent of shortening and dynamicity were additive. Thus, like the antimitotic mechanisms of action of the antitumor drugs vinblastine and taxol, the antimitotic mechanism of action of estramustine may be due to kinetic stabilization of spindle microtubule dynamics. The results may explain the mechanistic basis for the benefit derived from combined use of estramustine with vinblastine or taxol, two other drugs that target microtubules, in the treatment of hormone-refractory prostate cancer.

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Suppression of Microtubule Dynamics by LY290181

Cited by 68 publications

References 36 publications

Development of a Novel Nitro-Derivative of Noscapine for the Potential Treatment of Drug-Resistant Ovarian Cancer and T-Cell Lymphoma

Development of a Novel Nitro-Derivative of Noscapine for the Potential Treatment of Drug-Resistant Ovarian Cancer and T-Cell Lymphoma

Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death

Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: A possible mechanistic basis for its antitumor action

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