Glucocorticoids induce G1 arrest of lymphoblastic cells through retinoblastoma protein Rb1 dephosphorylation in childhood acute lymphoblastic leukemia in vivo.
Journal Title: Cancer Biology & Therapy - Year 2004, Vol 3, Issue 5
Abstract
Childhood Acute Lymphoblastic Leukemia (ALL) represents approximately 40% of pediatric cancers, but molecular mechanisms involved in the therapeutic resistance of ALL are still unclear. The disregulation of cell cycle could be a mechanism of progression of leukemic blasts and glucocorticoids (GCs), the main pharmacological agent in the treatment of ALL, could affect cell cycle distribution. In our study we have evaluated cell cycle distribution and the expression of several molecules involved in cell cycle regulation in blasts collected from 32 patients with ALL before and 48 h after treatment with GCs. A significant increase of the percentage of ALL blasts in G(0)/G(1) phase was recorded after treatment with GCs in 22 (69%) out of 32 patients and 18 of these patients were also good responders to GC therapy. In these patients an increase of the expression of at least one of the 4 evaluated CDKIs (p15, p16, p21 and p27) was found in 29 out of 32 patients (90.6%) without any change in CDK2 and 4 expression. All patients expressed detectable levels of Rb-1 phosphorylation at the diagnosis. Twenty (63%) patients showed a decrease, while two patients showed an increase of p110 Rb-1 phosphorylation and no changes were detected in the remaining 10 patients after GC therapy. The univariate analysis showed that the reduction of pRb-1 phosphorylation was significantly higher in B-cell lineage patients and in good responders. In conclusion, this is the first report that evaluate the Rb-1 function as predictor of response in childhood ALL and our data suggest that its hypophosphorylation and, consequently, reduced activity correlates with a statistical significance with the responsiveness to GC therapy. These results suggest that Rb-1 can be a useful molecular target for the therapy of this subset of patients.
Authors and Affiliations
Raffaele Addeo, Fiorina Casale, Michele Caraglia, Velia D'Angelo, Stefania Crisci, Alberto Abbruzzese, Maria Teresa Di Tullio, Paolo Indolfi
Keywords
Related Articles
- EP ID EP83894
- DOI -
- Views 72
- Downloads 0
Pharmacodynamic behavior of liposomal antisense oligonucleotides targeting Her-2/neu and vascular endothelial growth factor in an ascitic MDA435/LCC6 human breast cancer model.
The nature of anti-cancer therapeutics is currently undergoing a paradigm change, with biologic agents slowly being introduced into the therapeutic armory, displacing or complimenting the traditionally used cytotoxic age...
Glucocorticoids induce G1 arrest of lymphoblastic cells through retinoblastoma protein Rb1 dephosphorylation in childhood acute lymphoblastic leukemia in vivo.
Childhood Acute Lymphoblastic Leukemia (ALL) represents approximately 40% of pediatric cancers, but molecular mechanisms involved in the therapeutic resistance of ALL are still unclear. The disregulation of cell cycle co...
Prognostic role of bcl-xL and p53 in childhood acute lymphoblastic leukemia(ALL).
Molecular parameters involved in the prediction of response of childhoodacute lymphoblastic leukemia (ALL) are still unclear. We have evaluated the expression and mutationalstatus of p53 and the expression of bcl-x(L) an...