Mechanism of action of the Aurora kinase inhibitor CCT129202 and <i>in vivo</i> quantification of biological activity

Chan, Florence; Sun, Chongbo; Perumal, Meg; Nguyen, Quang-Dé; Bavetsias, Vassilios; McDonald, Edward; Martins, Vanessa; Wilsher, Nicola E.; Raynaud, Florence I.; Valenti, Melanie; Eccles, Sue; Poele, Robert te; Workman, Paul; Aboagye, Eric O.; Linardopoulos, Spiros

doi:10.1158/1535-7163.mct-07-2156

Cited by 63 publications

(55 citation statements)

References 39 publications

(59 reference statements)

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“…Of interest, where drug effects on proliferation are delayed, we see no early changes in tumor [ 18 F]FLT uptake, as shown in a recent study (26). The study design reported here is different from one that will be used clinically, i.e., pretreatment scans followed by posttreatment scans in the same patient, but is useful in that it permits direct comparison of the imaging end point to tumor biochemistry in individual animal tumors.…”

Section: Discussionmentioning

confidence: 65%

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Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901

Leyton

Smith

Lees

et al. 2008

Molecular Cancer Therapeutics

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Section: Discussionmentioning

confidence: 65%

“…18 F]FLT imaging studies in RIF-1 (14) and IGROV-1 (15), we found no differences between radiotracer uptake/biochemical variables in size-matched untreated tumors versus tumors treated with vehicle for 1 day, and therefore, as with recent studies, we compared day 1 vehicle-treated to day 1 drug-treated groups (13,26). The lower […”

Section: Discussionmentioning

confidence: 66%

Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901

Leyton

Smith

Lees

et al. 2008

Molecular Cancer Therapeutics

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“…Indeed, down-regulation of cdk 2 activity and the appearance of the fastest migrating form of Rb on immunoblot (representing both un-and hypo-phosphorylated Rb; Ezhevsky et al, 2001) has been correlated with exit from an aberrant mitosis into a pseudo G1 phase (Lanni and Jacks, 1998;Motwani et al, 1999Motwani et al, , 2000Chan et al, 2007). Rbnegative cells are more susceptible to polyploidy induction in response to a variety of stimuli, including treatment with mitotic spindle poisons (Di Leonardo et al, 1997), exogenous p21 expression (Niculescu et al, 1998), and ionizing radiation (Avni et al, 2003), consistent with a model in which hypophosphorylated Rb inhibits endoreduplication and polyploidy.…”

Section: Discussionmentioning

confidence: 99%

Aurora B Kinase Regulates the Postmitotic Endoreduplication Checkpoint via Phosphorylation of the Retinoblastoma Protein at Serine 780

Nair

Tse

et al. 2009

MBoC

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The phenotypic change characteristic of Aurora B inhibition is the induction of polyploidy. Utilizing specific siRNA duplexes and a selective small molecule inhibitor (AZD1152) to inhibit Aurora B activity in tumor cells, we sought to elucidate the mechanism by which Aurora B inhibition results in polyploidy. Cells treated with AZD1152 progressed through mitosis with misaligned chromosomes and exited without cytokinesis and subsequently underwent endoreduplication of DNA despite activation of a p53-dependent pseudo G1 checkpoint. Concomitant with polyploid cell formation, we observed the appearance of Rb hypophosphorylation, an event that occurred independently of cyclindependent kinase inhibition. We went on to discover that Aurora B directly phosphorylates Rb at serine 780 both in vitro and in vivo. This novel interaction plays a critical role in regulating the postmitotic checkpoint to prevent endoreduplication after an aberrant mitosis. Thus, we propose for the first time that Aurora B determines cellular fate after an aberrant mitosis by directly regulating the Rb tumor suppressor protein.

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“…Inhibiting Aurora A and Aurora B kinases with the inhibitor CCT129202 causes tumor cells to accumulate with a greater than 4N DNA content and undergo apoptosis, reduces double minute 2 (MDM2) levels, and induces the stability of p53 and p21. Inhibition of these aurora kinases also results in hypo-phosphorylation of RB, downregulation of thymidine kinase 1, reduced phosphorylation of histone H3, and increased cleavage of PARP (35).…”

Section: Introductionmentioning

confidence: 99%

Conditional ablation of Ikkb inhibits melanoma tumor development in mice

et al. 2010

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Several lines of evidence suggest that tumor cells show elevated activity of the NF-κB transcription factor, a phenomenon often resulting from constitutive activity of IκB kinase β (IKKβ). However, others have found that loss of NF-κB activity or IKKβ is tumor promoting. The role of NF-κB in tumor progression is therefore controversial and varies with tumor type. We sought to more extensively investigate the role IKKβ in melanoma tumor development by specifically disrupting Ikkb in melanocytes in an established mouse model of spontaneous melanoma, whereby HRas V12 is expressed in a melanocyte-specific, doxycycline-inducible manner in mice null for the gene encoding the tumor suppressor inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf). Our results show that Ink4a/Arf -/-mice with melanocyte-specific deletion of Ikkb were protected from HRas V12 -initiated melanoma only when p53 was expressed. This protection was accompanied by cell cycle arrest, with reduced cyclin-dependent kinase 2 (Cdk2), Cdk4, Aurora kinase A, and Aurora kinase B expression. Increased p53-mediated apoptosis was also observed, with decreased expression of the antiapoptotic proteins Bcl2 and survivin. Enhanced stabilization of p53 involved increased phosphorylation at Ser15 and reduced phosphorylation of double minute 2 (Mdm2) at Ser166. Together, our findings provide genetic and mechanistic evidence that mutant HRas initiation of tumorigenesis requires Ikkβ-mediated NF-κB activity.

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Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity

Abstract: The Aurora family of serine

Cited by 63 publications

References 39 publications

Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901

Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901

Aurora B Kinase Regulates the Postmitotic Endoreduplication Checkpoint via Phosphorylation of the Retinoblastoma Protein at Serine 780

Conditional ablation of Ikkb inhibits melanoma tumor development in mice

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