In vitro sensitivity of T-cell lymphoblastic leukemia to UCN-01 (7-hydroxystaurosporine) is dependent on p16 protein status: a Pediatric Oncology Group study

M Omura-Minamisawa; M B Diccianni; A Batova; R C Chang; L J Bridgeman; J Yu; E de Wit; F H Kung; J D Pullen; A L Yu

In vitro sensitivity of T-cell lymphoblastic leukemia to UCN-01 (7-hydroxystaurosporine) is dependent on p16 protein status: a Pediatric Oncology Group study

Cancer Res. 2000 Dec 1;60(23):6573-6.

Authors

M Omura-Minamisawa¹, M B Diccianni, A Batova, R C Chang, L J Bridgeman, J Yu, E de Wit, F H Kung, J D Pullen, A L Yu

Affiliation

¹ Department of Pediatrics/Hematology-Oncology, University of California, San Diego 92103-8447, USA.

PMID: 11118035

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Alkaloids / toxicity*
Antineoplastic Agents / toxicity*
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
Humans
Leukemia-Lymphoma, Adult T-Cell / drug therapy*
Leukemia-Lymphoma, Adult T-Cell / genetics
Leukemia-Lymphoma, Adult T-Cell / metabolism
Phosphorylation
Retinoblastoma Protein / biosynthesis
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Staurosporine / analogs & derivatives
Tumor Cells, Cultured
Tumor Suppressor Proteins*

Substances

Alkaloids
Antineoplastic Agents
CDKN2B protein, human
Carrier Proteins
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p16
Retinoblastoma Protein
Tumor Suppressor Proteins
7-hydroxystaurosporine
Staurosporine

Grants and funding

etc