VX-680 Inhibits Aurora A and Aurora B Kinase Activity in Human Cells

Tyler, Rebecca K.; Shpiro, Natalia; Marquez, Rodolfo; Eyers, Patrick A.

doi:10.4161/cc.6.22.4940

Cited by 108 publications

(111 citation statements)

References 38 publications

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“…4 Thus, aberrant mitotic events, such as lagging chromosome and spindles with reduced microtubule contents, caused by treatment of TACC3 siRNA were also observed in cells treated with Aurora-A inhibitor which blocks TACC3 spindle association. 2,[5][6][7][8][9] More recently, a study using inducible TACC3 siRNA revealed that TACC3 depletion also induces a p21 WAF -mediated G 0 /G 1 phase cell arrest, depicting a distinct role of TACC3 in regulating cell cycle. 10 Furthermore, TACC3 expression level was reported to be upregulated in several cancer types such as ovarian cancer, thyroid cancer and non-small cell lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Cdh1 controls the stability of TACC3

Jeng¹,

Lin²,

Lin³

et al. 2009

Cell Cycle

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Section: Introductionmentioning

confidence: 99%

Cdh1 controls the stability of TACC3

Jeng¹,

Lin²,

Lin³

et al. 2009

Cell Cycle

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“…Examples are Hesperadin (10), ZM447439 (9), and AZD1152 (14), which show selectivity for Aurora-B in vivo and VX-680 (MK-0547), which inhibits both Aurora-A and Aurora-B (15,16). Most recently, the first Aurora-A selective inhibitor, MLN8054, has been introduced (17).…”

Section: Introductionmentioning

confidence: 99%

Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells

Kaestner

Stolz²,

Bastians³

2009

Molecular Cancer Therapeutics

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The mitotic Aurora kinases, including Aurora-A and Aurora-B, are attractive novel targets for anticancer therapy, and inhibitory drugs have been developed that are currently undergoing clinical trials. However, the molecular mechanisms how these drugs induce tumor cell death are poorly understood. We have addressed this question by comparing the requirements for an efficient induction of apoptosis in response to MLN8054, a selective inhibitor of Aurora-A, and the selective Aurora-B inhibitor ZM44-7439 in human colon carcinoma cells. By using various isogenic knockout as well as inducible colon carcinoma cell lines, we found that treatment with MLN8054 induces defects in mitotic spindle assembly, which causes a transient spindle checkpoint-dependent mitotic arrest. This cell cycle arrest is not maintained due to the activity of MLN8054 to override the spindle checkpoint. Subsequently, MLN8054-treated cells exit from mitosis and activate a p53-dependent postmitotic G 1 checkpoint, which subsequently induces p21 and Bax, leading to G 1 arrest followed by the induction of apoptosis. In contrast, inhibition of Aurora-B by ZM447439 also interferes with normal chromosome alignment during mitosis and overrides the mitotic spindle checkpoint but allows a subsequent endoreduplication, although ZM447439 potently activates the p53-dependent postmitotic G 1 checkpoint. Moreover, the ZM447439-induced endoreduplication is a prerequisite for the efficiency of the drug. Thus, our results obtained in human colon carcinoma cells indicate that although both Aurora kinase inhibitors are potent inducers of tumor cell death, the pathways leading to the induction of apoptosis in response to these drugs are distinct.

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“…22 VX680 inhibits the activities of both the Aurora A and B kinases. 23 VX680 has been reported to inhibit the growths of cancer cells of various origins by causing cell cycle arrest and apoptosis. In a phase I/II study, VX680 was proven to be active in patients with refractory hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

Jin

Zhang

et al. 2016

Cancer Biology & Therapy

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VX680 is a potent and selective inhibitor that targets the Aurora kinase family. The p38 mitogen-activated protein kinase (MAPK) regulates a large number of cellular pathways and plays an important role in the regulation of cell survival and apoptosis. This study aimed to evaluate the effect of VX680 on cervical cancer cells and investigate whether the effects on apoptosis are enhanced by the ablation of p38 MAPK activation. The results suggested that VX680 inhibited the proliferation of cervical cancer cells by causing G2/M phase arrest and endoreduplication and that the apoptotic effect was attenuated by the activation of p38 MAPK. However, the addition of BIRB796, which is an important p38 MAPK inhibitor, effectively eliminated the expression of p-p38 and hence significantly enhanced the cell death induced by VX680 in vitro. Further study demonstrated that BIRB796 cooperated with VX680 to suppress cervical cancer cell growth in a mouse xenograft model. Taken together, our results demonstrated that VX680 induced cell cycle arrest and endoreduplication in human cervical cancer cells. Combined treatment with VX680 and BIRB796 synergistically inhibited tumor growth both in vitro and in vivo. Dual blockade of Aurora kinases and p38 MAPK is therefore a promising strategy for cervical cancer treatment.

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VX-680 Inhibits Aurora A and Aurora B Kinase Activity in Human Cells

Cited by 108 publications

References 38 publications

Cdh1 controls the stability of TACC3

Cdh1 controls the stability of TACC3

Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

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