Effects of the Aurora kinase inhibitor VX-680 on anaplastic thyroid cancer-derived cell lines

Arlot‐Bonnemains, Yannick; Baldini, Enke; Martin, Bénédicte; Delcros, Jean‐Guy; Toller, Matteo; Curcio, Francesco; Ambesi-Impiombato, Francesco Saverio; D’Armiento, Massimino; Ulisse, Salvatore

doi:10.1677/erc-08-0021

Cited by 55 publications

(52 citation statements)

References 43 publications

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“…Moreover, the immunemediated injury to peritumoral tissues as well as the potential onset of autoimmune diseases might represent important therapeutic barriers. Unlike ADZ1152, MLN8237 was able to activate apoptosis in all the ATC cells tested and, compared with AZD1152, displayed IC 50 values closer to those that we previously obtained with the pan-inhibitors of Aurora kinases SNS-314 and VX-680 for the same cell lines by means of the same proliferation assay used in this study (Arlot-Bonnemains et al 2008, Baldini et al 2012a.…”

Section: Figuresupporting

confidence: 82%

“…In recent years, our group has analyzed the effects of some small molecule pan-inhibitors of Aurora kinases, including VX-680/MK-0457 (Arlot-Bonnemains et al 2008), SNS-314 (Baldini et al 2012b), and ZM447439 (Baldini et al 2013), on human ATC-derived cell lines. Our findings indicated that all the inhibitors reduced considerably the growth and survival of the different ATC cells tested, which prompted us to further explore the anti-tumoral properties of this class of compounds.…”

Section: Introductionmentioning

confidence: 99%

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Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

Baldini¹,

Tuccilli²,

Prinzi³

et al. 2014

Endocrine Related Cancer

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Aurora kinases are serine/threonine kinases that play an essential role in cell division. Their aberrant expression and/or function induce severe mitotic abnormalities, resulting in either cell death or aneuploidy. Overexpression of Aurora kinases is often found in several malignancies, among which is anaplastic thyroid carcinoma (ATC). We have previously demonstrated the in vitro efficacy of Aurora kinase inhibitors in restraining cell growth and survival of different ATC cell lines. In this study, we sought to establish which Aurora might represent the preferential drug target for ATC. To this end, the effects of two selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) on four human ATC cell lines (CAL-62, BHT-101, 8305C, and 8505C) were analysed. Both inhibitors reduced cell proliferation in a time-and dose-dependent manner, with IC 50 ranges of 44.3-134.2 nM for MLN8237 and of 9.2-461.3 nM for AZD1152. Immunofluorescence experiments and time-lapse videomicroscopy yielded evidence that each inhibitor induced distinct mitotic phenotypes, but both of them prevented the completion of cytokinesis. As a result, poliploidy increased in all AZD1152-treated cells, and in two out of four cell lines treated with MLN8237. Apoptosis was induced in all the cells by MLN8237, and in BHT-101, 8305C, and 8505C by AZD1152, while CAL-62 exposed to AZD1152 died through necrosis after multiple rounds of endoreplication. Both inhibitors were capable of blocking anchorage-independent cell growth. In conclusion, we demonstrated that either Aurora-A or Aurora-B might represent therapeutic targets for the ATC treatment, but inhibition of Aurora-A appears more effective for suppressing ATC cell proliferation and for inducing the apoptotic pathway.

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Section: Figuresupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

Baldini¹,

Tuccilli²,

Prinzi³

et al. 2014

Endocrine Related Cancer

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“…S ULISSE and others 139 per h, the maximal plasma concentration recorded was 650 nM, similar to that causing regressions in xenografts and well above the dose used in the present study (Harrington et al 2004, Rubin et al 2006, Mountzios et al 2008. Aurora-A kinase activity is required for the phosphorylation and localization of different proteins in the pericentrosomal area, involved in the mitotic spindle assembly (Carmena & Earnshaw 2004, Vagnarelli & Earnshaw 2004, Mori et al 2007, Ulisse et al 2007, Arlot-Bonnemains et al 2008. Accordingly, we found that the treatment of NT2-D1 cells with MK-0457 causes major alterations in centrosome functions with abnormal spindle formation characterized by the presence of short microtubules.…”

Section: Discussionsupporting

confidence: 78%

“…These findings have led to their evaluation as a potential target for anticancer therapy (Harrington et al 2004, Hata et al 2005, Matthew et al 2006, Manfredi et al 2007, Arlot-Bonnemains et al 2008, Mountzios et al 2008. TGCTs are characterized, as other types of solid tumors, by aneuploidy, and show an altered expression pattern of the aurora kinases (Oosterhuis et al 1989, Roelofs et al 2000, Chieffi et al 2004, Korkola et al 2008, Baldini et al 2010.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the aurora kinases suppresses in vitro NT2-D1 cell growth and tumorigenicity

Ulisse¹,

Arlot‐Bonnemains²,

Baldini³

et al. 2009

Journal of Endocrinology

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The aurora kinase family members, Aurora-A, -B, and -C (listed as AURKA, AURKB and AURKC respectively in the HUGO Database), are serine/threonine kinases involved in the regulation of chromosome segregation and cytokinesis, and alterations in their expression are associated with malignant cell transformation and genomic instability. Deregulation of the expression of the aurora kinases has been shown to occur also in testicular germ cell tumors (TGCTs) identifying them as putative anticancer therapeutic targets. We here evaluated the in vitro effects of MK-0457, an aurora kinases inhibitor, on cell proliferation, cell cycle, ploidy, apoptosis, and tumorigenicity on the TGCT-derived cell line NT2-D1. Treatment with MK-0457 inhibited cell proliferation in a time-and dosedependent manner, with IC 50 Z17 . 2G3 . 3 nM. MK-0457 did not affect the expression of the three aurora kinases, but prevented their ability to phosphorylate substrates relevant to the mitotic progression. Time-lapse experiments demonstrated that MK-0457-treated cells entered mitosis but were unable to complete it, presenting after short time the typical features of apoptotic cells. Cytofluorimetric analysis confirmed that the treatment with MK-0457 for 6 h induced NT2-D1 cells accumulation in the G 2 /M phase of the cell cycle and the subsequent appearance of sub-G 0 nuclei. The latter result was further supported by the detection of caspase-3 activation following 24-h treatment with the inhibitor. Finally, MK-0457 prevented the capability of the NT2-D1 cells to form colonies in soft agar. In conclusion, the above findings demonstrate that inhibition of aurora kinase activity is effective in reducing in vitro growth and tumorigenicity of NT2-D1 cells, and indicate its potential therapeutic value for TGCT treatment.

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“…For instance, a microarray analysis suggested that TACC3 is upregulated during the transition of ductal carcinoma in situ to invasive ductal carcinoma, while an immunohistochemical analysis demonstrated that TACC3 is downregulated in resected breast tumors (18,19). A similar discrepancy was found in the expression of TACC3 in ovarian tumor and thyroid cancer (20)(21)(22). In addition, TACC3 has been identified as a potential glioblastoma multiforme oncogene and may be overexpressed in multiple myeloma cases and lung cancer (23)(24)(25).…”

Section: Introductionmentioning

confidence: 95%

The clinical significance of transforming acidic coiled-coil protein 3 expression in non-small cell lung cancer

et al. 2015

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Abstract.The relationship between TACC3, a member of the transforming acidic coiled-coil proteins (TACCs) family, and lung carcinoma remains unclear. The present study was designed to explore the prognostic and clinical significance of TACC3 in non-small cell lung cancer (NSCLC). An immunohistochemistry (IHC) assay was performed to analyze the expression of TACC3 in 195 lung cancer cases. The mRNA and protein levels of TACC3 were examined by quantitative reverse transcription-PCR or western blotting. The correlation between TACC3 expression and clinicopathological factors was analyzed by χ 2 analysis and Fisher's exact test. Kaplan-Meier analysis and the Cox proportional hazards model were used to examine the correlation of prognostic outcomes with TACC3. The results showed that the levels of TACC3 mRNA and total protein were higher in lung cancer lesions than paired non-cancerous tissues. IHC analysis revealed that TACC3 was highly expressed in 94 (48.2%) cases. The expression of TACC3 was strongly correlated with smoking status, histological classification, differentiation, cytokeratin 19 fragment levels, T stage and the clinical stage of NSCLC patients. Univariate and multivariate analyses demonstrated that TACC3 is a useful biomarker for NSCLC prognosis. The low TACC3 expression group exhibited better progression-free survival (PFS) among patients who received anti-microtubule chemotherapy. In conclusion, the results showed that a high level of TACC3 expression was correlated with advanced clinicopathological classifications, poor overall survival (OS) and poor recurrence-free survival (RFS) in NSCLC patients.Our findings indicate that TACC3 is a potential prognostic marker and therapeutic target for NSCLC.

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Effects of the Aurora kinase inhibitor VX-680 on anaplastic thyroid cancer-derived cell lines

Cited by 55 publications

References 43 publications

Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

Inhibition of the aurora kinases suppresses in vitro NT2-D1 cell growth and tumorigenicity

The clinical significance of transforming acidic coiled-coil protein 3 expression in non-small cell lung cancer

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