SU9516 is a selective cdk2 inhibitor and support the theory that compounds that inhibit cdk2 are viable resources in the development of new antineoplastic agents. SU9516 is 9-fold and 1.8-fold more selective for cdk2 than cdk4 and cdk1, respectively. Treatment with SU9516 (5 μM) inhibited (P ≤ 0.05) both cdk2-specific (27–64%) and cdk4-specific (26–49%) phosphorylation of pRb in SW480 cells at all (24, 48, and 72 h) time points. RKO cells remained blocked in G2-M at 20 h post-serum induction and -addition of SU9516. SU9516 produced a dose-dependent G1 accumulation in EGF-stimulated cells.Treatment with 5 microM SU9516 prevented dissociation of pRb from E2F1 in all cell lines (HT-29>RKO>SW480). Treatment effects were time-dependent, demonstrating greater inhibition at 48 hr versus 24hr in HT-29 cells. Furthermore, E2F species were sequestered in complexes with p107, p130, DP-1, and cyclins A and E. After a 24-hr treatment with 5 microM SU9516, cyclin D1 and cdk2 levels decreased by 10-60%. Exposure of U937 and other leukemia cells to SU9516 concentrations > or =5 microM rapidly (i.e., within 4 h) induced cytochrome c release, Bax mitochondrial translocation, and apoptosis in association with pronounced down-regulation of the antiapoptotic protein Mcl-1.
|Cell lines||RKO cells and SW480 cells|
|Preparation method||Seeding RKO cells and SW480 cells in replicates in 96-well plates at 1 × 104 cells/well and allowing to attach overnight. adding SU9516 in concentrations from 0.05 μM to 50.00 μM for 24 h, then washing the cells twice with PBS, and replenishing cells with complete media. Fixing the cells at 0, 4, and 7 days post-drug removal and assaying for protein levels using a modified SRB cytotoxicity assay.Fixing the cells in 10% trichloroacetic acid for 1 h, washing in distilled H2O, and staining in 0.4% SRB/acetic acid for 30 min. Then washing the cells in 0.1% acetic acid, solubilizing in 10 mM Tris (pH 9), and analyzing on a Bio-Rad 360 microplate reader at 595 nm. Repeating all experiments at least three times.|
|Incubation time||24 hours|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
The three-substituted indolinone cyclin-dependent kinase 2 inhibitor 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) kills human leukemia cells via down-regulation of Mcl-1 through a transcriptional mechanism.
Gao N, et al. Mol Pharmacol. 2006 Aug;70(2):645-55. PMID: 16672643.
SU9516: biochemical analysis of cdk inhibition and crystal structure in complex with cdk2.
Moshinsky DJ, et al. Biochem Biophys Res Commun. 2003 Oct 24;310(3):1026-31. PMID: 14550307.
SU9516, a cyclin-dependent kinase 2 inhibitor, promotes accumulation of high molecular weight E2F complexes in human colon carcinoma cells.
Yu B, et al. Biochem Pharmacol. 2002 Oct 1;64(7):1091-100. PMID: 12234612.
A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells.
Lane ME, et al. Cancer Res. 2001 Aug 15;61(16):6170-7. PMID: 11507069.
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