Mitotic drivers—inhibitors of the Aurora B Kinase

Keen, Nicholas; Taylor, Stephen S.

doi:10.1007/s10555-009-9184-9

Cited by 63 publications

(62 citation statements)

References 48 publications

(70 reference statements)

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“…Since Aurora B kinase is required for completion of mitosis, chromosome segregation and cytokinesis, and is up-regulated in a variety of tumors, it is considered as relevant target in cancer therapy [40,41]. In this context, AZD1152, another Aurora B kinase inhibitor, blocks proliferation in human breast cancer cell lines and reduces lung metastasis of MDA-MB-231 in nude mouse [42].…”

Section: Discussionmentioning

confidence: 99%

Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells

Sánchez-Bailón

Calcabrini

Gómez-Domínguez

et al. 2012

Cellular Signalling

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SFKs are frequently deregulated in cancer where they control cellular proliferation, migration, survival and metastasis. Here we study the role of SFKs catalytic activity in triple-negative/basal-like and metastatic human breast cancer MDA-MB-231 cells employing three well-established inhibitors: Dasatinib, PP2 and SU6656. These compounds inhibited migration and invasion. Concomitantly, they reduced Fak, paxillin, p130CAS, caveolin-1 phosphorylation and altered cytoskeletal structures. They also inhibited cell proliferation, but in different manners. Dasatinib and PP2 increased p27Kip1 expression and reduced c-Myc levels, restraining G1-S transition. In contrast, SU6656 did not modify p27Kip1 expression, slightly altered c-Myc levels and generated polyploid multinucleated cells, indicating inhibition of cytokinesis. These later effects were also observed in SYF fibroblasts, suggesting a SFKs-independent action. ZM447439, an Aurora B kinase inhibitor, produced similar cell cycle and morphological alterations in MDA-MB-231 cells, indicating that SU6656 blocked Aurora B kinase. This was confirmed by inhibition of histone H3 phosphorylation, the canonical Aurora B kinase substrate. Furthermore, hierarchical clustering analysis of gene expression profiles showed that SU6656 defined a set of genes that differed from Dasatinib and PP2. Additionally, Gene Set Enrichment Analyses revealed that SU6656 significantly reduces the Src pathway. Together, these results show the importance of SFKs catalytic activity for MDA-MB-231 proliferation, migration and invasiveness. They also illustrate that SU6656 acts as dual SFKs and Aurora B kinase inhibitor, suggesting its possible use as a therapeutic agent in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells

Sánchez-Bailón

Calcabrini

Gómez-Domínguez

et al. 2012

Cellular Signalling

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“…The ATP-binding pocket of protein kinases represents an ideal target for pharmacological therapy, and differences in the nature of residues lining the ATP-binding cavity explain the selectivity of many kinase inhibitors [13,20]. Hesperadin as an inhibitor of ATP-binding site of Aurora kinase inhibits the activity of Aurora kinase B with IC50 values of 250 nM in vitro [14].…”

Section: Discussionmentioning

confidence: 99%

“…When Aurora B is inhibited, cells fail to biorient their chromosomes and resulting in induction of polyploidy in cells as a consequence of cytokinesis failure [13]. On the other hand, high-level expression of Aurora B in model systems has been linked to chromosome instability [12,18].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and investigation of new Hesperadin analogues antitumor effects on HeLa cells

et al. 2014

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Hesperadin is one of the indolinones that was designed against the ATP-binding site of Aurora kinase. This molecule inhibits Aurora B kinase by phosphorylation of histone H3. In this study, new derivatives of Hesperadin containing an amide group in their structures were synthesized through sequential Ugi/palladium-catalyzed approach and in vitro antitumor activity of new compounds were evaluated by cell proliferation assay. The results show that compounds 6f, 6i, 6l, and 6o were dose-dependently inhibited in different concentrations, and IC50 values were between 35 and 43 nM. It seems that lipophilic substitution on the indolinone core with the ability to form additional hydrogen bond might lead to increased stability of structure and activity of new Hesperadin analogues.

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“…This inhibition results in efficient cell killing in a variety of tumor cell lines (Ditchfield et al, 2003;Hauf et al, 2003;Harrington et al, 2004;Kaestner et al, 2009) and does not seem to have a prominent effect on non-dividing cells, which makes it an interesting, proliferation-specific anti-cancer target (Ditchfield et al, 2003). Several Aurora B inhibitors have been generated and some have entered clinical trials (Keen and Taylor, 2009).…”

Section: Inducing Tetraploidymentioning

confidence: 99%

“…Promising effects of these inhibitors, some of which also target Aurora A, have been seen in mouse tumor models (Harrington et al, 2004;Wilkinson et al, 2007;Oke et al, 2009) and patients with various types of tumors (Keen and Taylor, 2009;Lok et al, 2010) (Table 1).…”

Section: Inducing Tetraploidymentioning

confidence: 99%