In vitro sensitivity of T-cell lymphoblastic leukemia to UCN-01 (7-hydroxystaurosporine) is dependent on p16 protein status: a Pediatric Oncology Group study.
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.
Omura-Minamisawa
M
M
Department of Pediatrics/Hematology-Oncology, University of California, San Diego 92103-8447, USA.
Diccianni
M B
MB
Batova
A
A
Chang
R C
RC
Bridgeman
L J
LJ
Yu
J
J
de Wit
E
E
Kung
F H
FH
Pullen
J D
JD
Yu
A L
AL
D000470:Alkaloids / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D000470:Alkaloids; D000970:Antineoplastic Agents; C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; C054852:7-hydroxystaurosporine; D019311:Staurosporine