In vitro sensitivity of T-cell lymphoblastic leukemia to UCN-01 (7-hydroxystaurosporine) is dependent on p16 protein status : A pediatric oncology group study

• Published in: Cancer research (Chicago, Ill.) Ill.), 2000-12, Vol.60 (23), p.6573-6576
• Main Authors: OMURA-MINAMISAWA, Motoko, DICCIANNI, Mitchell B, BATOVA, Ayse, CHANG, Ray C, BRIDGEMAN, Louis J, YU, John, DE WIT, Esther, KUNG, Faith H, PULLEN, Jeanette D, YU, Alice L
• Format: Article
• Language: English
• Subjects: 7-hydroxystaurosporine; Alkaloids - toxicity; Antineoplastic agents; Antineoplastic Agents - toxicity; Biological and medical sciences; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - physiology; Gene Deletion; Gene Expression Regulation, Leukemic; Gene Silencing; General aspects; Humans; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - metabolism; Medical sciences; p16 protein; Pharmacology. Drug treatments; Phosphorylation; Retinoblastoma Protein - biosynthesis; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Staurosporine - analogs & derivatives; Tumor Cells, Cultured; Tumor Suppressor Proteins
• ISSN: 0008-5472; 1538-7445

p16 regulates the cell cycle pathway by inhibiting the cyclin Ds-cyclin-dependent kinase (CDK) 4/6-mediated phosphorylation of retinoblastoma protein (pRb). Previously, we reported that most primary T-cell acute lymphoblastic leukemia (T-ALL) harbored p16 inactivation and hyperphosphorylated pRb without cyclin Ds or CDK4/6 alterations. Therefore, inhibiting CDK4/6 may be an ideal therapeutic approach for p16 (-) T-ALL. UCN-01 (7-hydroxystaurosporine) is a potent antitumor agent that exerts its effects through the inhibition of CDKs. We now report that p16 protein expression status of T-ALL cells influences their sensitivity to UCN-01. In 36 primary T-ALL cells, the IC50s of UCN-01 in the 27 p16 (-) cells (43+/-52 nM) was significantly lower than that in the 9 p16 (+) cells (258+/-260 nM). Our results suggest that agents like UCN-01 may be useful as a p16-selective therapy for T-ALL.