A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 16; pp. 6170 - 6177
• Main Authors: LANE, Maureen E, YU, Bo, RICE, Audie, LIPSON, Kenneth E, LIANG, Chris, LI SUN, CHO TANG, MCMAHON, Gerald, PESTELL, Richard G, WADLER, Scott
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2001
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; CDC2-CDC28 Kinases; Cell Division - drug effects; Chemotherapy; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases - antagonists & inhibitors; Enzyme Inhibitors - pharmacology; Growth Inhibitors - pharmacology; Humans; Imidazoles - pharmacology; Indoles - pharmacology; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Retinoblastoma Protein - metabolism; Substrate Specificity; Tumor Cells, Cultured; Antineoplastic agent; Human; Cell proliferation; Carcinoma; Enzyme; Transferases; Enzyme inhibitor; Malignant tumor; In vitro; Biological activity; Colonic disease; Signal transduction; Cell death; Protein kinase; Established cell line; Digestive diseases; Intestinal disease; Colon; Mechanism of action; Subtype; Tumor cell; Apoptosis
• ISSN: 0008-5472

Recent studies have indicated that the development of cyclin-dependent kinase (cdk)2 inhibitors that deregulate E2F are a plausible pharmacological strategy for novel antineoplastic agents. We show here that 3-[1-(3H-Imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516), a novel 3-substituted indolinone compound, binds to and selectively inhibits the activity of cdk2. This inhibition results in a time-dependent decrease (4-64%) in the phosphorylation of the retinoblastoma protein pRb, an increase in caspase-3 activation (5-84%), and alterations in cell cycle resulting in either a G(0)-G(1) or a G(2)-M block. We also report here cell line differences in the cdk-dependent phosphorylation of pRb. These findings demonstrate that 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.