Rational Design of the Microtubule-Targeting Anti–Breast Cancer Drug EM015

Aneja, Ritu; Lopus, Manu; Zhou, Jun; Vangapandu, Surya N.; Ghaleb, Amr M.; Yao, Joyce; Nettles, James H.; Zhou, Baohua; Gupta, Meenakshi V.; Panda, Dulal; Chandra, Ramesh; Joshi, Harish C.

doi:10.1158/0008-5472.can-05-2962

Cited by 56 publications

(56 citation statements)

References 32 publications

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“…The affinity of carbendazim for tubulin is less than that of benomyl, most probably because it lacks the position 1 side chain of benomyl. Although the affinity of carbendazim for tubulin is relatively weak, it is similar to that of other investigatory cancer drugs, such as the noscapine analog EM015 (K d , 40 Ϯ 8 M) (Aneja et al, 2006).…”

Section: Loss Of Intercentromere Tension Indicates Suppression Of Mitmentioning

confidence: 73%

Carbendazim Inhibits Cancer Cell Proliferation by Suppressing Microtubule Dynamics

Mythili

Cox²,

Wilson³

et al. 2008

J Pharmacol Exp Ther

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Carbendazim (methyl 2-benzimidazolecarbamate) is widely used as a systemic fungicide in human food production and appears to act on fungal tubulin. However, it also inhibits proliferation of human cancer cells, including drug-and multidrug-resistant and p53-deficient cell lines. Because of its promising preclinical antitumor activity, it has undergone phase I clinical trials and is under further clinical development. Although it weakly inhibits polymerization of brain microtubules and induces G 2 /M arrest in tumor cells, its mechanism of action in human cells has not been fully elucidated. We examined its mechanism of action in MCF7 human breast cancer cells and found that it inhibits proliferation (IC 50 , 10 M) and half-maximally arrests mitosis at a similar concentration (8 M), in concert with suppression of microtubule dynamic instability without appreciable microtubule depolymerization. It induces mitotic spindle abnormalities and reduces the metaphase intercentromere distance of sister chromatids, indicating reduction of tension on kinetochores, thus leading to metaphase arrest. With microtubules assembled in vitro from pure tubulin, carbendazim also suppresses dynamic instability, reducing the dynamicity by 50% at 10 M, with only minimal (

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Section: Loss Of Intercentromere Tension Indicates Suppression Of Mitmentioning

confidence: 73%

Carbendazim Inhibits Cancer Cell Proliferation by Suppressing Microtubule Dynamics

Mythili

Cox²,

Wilson³

et al. 2008

J Pharmacol Exp Ther

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“…Among the oral taxanes currently under preclinical testing, the seco-taxane derivative IDN 5390, for instance, has demonstrated important antitumour and anti-angiogenic properties in a paclitaxel-resistant ovarian cancer xenograft model [211]. Similarly, the rationally designed taxane EM015 has been reported to be efficient against several breast cancer cell lines regardless of the multi-drug resistance phenotype as well as in tumour xenografts, without any major toxicity [267]. The ongoing clinical development of taxanes can be also illustrated by the fact that one of these compounds (BMS-275183) has undergone phase I trial [268].…”

Section: New Agents and Formulation Issuesmentioning

confidence: 99%

Targeting Microtubules to Inhibit Angiogenesis and Disrupt Tumour Vasculature:Implications for Cancer Treatment

Pasquier¹,

André²,

Braguer³

2007

CCDT

127

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Anticancer agents that interfere with tubulin functions are widely used in the clinic and have a broad spectrum of activity against both haematological malignancies and solid tumours. These Microtubule-Targeting Agents (MTAs), such as the taxanes and Vinca alkaloids, bind to the beta subunit of alpha/beta tubulin and disrupt microtubule dynamics in tumour cells, ultimately leading to mitotic block and subsequent cell death. Recently, MTAs have received considerable interest as potential tumour-selective anti-angiogenic and vascular-disrupting agents. Angiogenesis is a keystone of tumour progression and metastasis and targeting the formation of new blood vessels within the tumour is therefore regarded as a promising strategy for cancer therapy. In this regard, conventional MTAs can be given on daily schedules at non-toxic doses (metronomic dosing) to disturb tumour angiogenesis. Some MTAs can also act as vascular-disrupting agents. After briefly reviewing the classical mechanisms involved in the anti-tumour action of MTAs, we will focus on the latest studies investigating the molecular and cellular processes underlying the anti-angiogenic and the vascular-disrupting properties of these agents. We will also review and discuss the potential clinical development and the limitations of MTAs used as tumour-specific anti-vascular molecules.

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“…1A, upper panels). We have previously reported the dissociation constant (K d ) of 144 AE 2.8 mM for noscapine binding to tubulin [18], 54 AE 9.1 mM for 9-Br-nos [12] binding to tubulin and 40 AE 8mM for 9-Cl-nos [43] binding to tubulin. The double reciprocal plots yielded a dissociation constant (K d ) of 81 AE 8 mM for 9-F-nos, and 22 AE 4mM for 5-I-nos, binding to tubulin.…”

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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Rational Design of the Microtubule-Targeting Anti–Breast Cancer Drug EM015

Cited by 56 publications

References 32 publications

Carbendazim Inhibits Cancer Cell Proliferation by Suppressing Microtubule Dynamics

Carbendazim Inhibits Cancer Cell Proliferation by Suppressing Microtubule Dynamics

Targeting Microtubules to Inhibit Angiogenesis and Disrupt Tumour Vasculature:Implications for Cancer Treatment

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

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