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Titolo:
Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells
Autore:
Porosnicu, M; Nimmanapalli, R; Nguyen, D; Worthington, E; Perkins, C; Bhalla, KN;
Indirizzi:
Univ S Florida, Interdisciplinary Oncol Program, Moffit Canc Ctr, Tampa, FL 33612 USA Univ S Florida Tampa FL USA 33612 m, Moffit Canc Ctr, Tampa, FL 33612 USA Univ Miami, Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL USA Univ Miami Miami FL USA ed, Sylvester Comprehens Canc Ctr, Miami, FL USA
Titolo Testata:
LEUKEMIA
fascicolo: 5, volume: 15, anno: 2001,
pagine: 772 - 778
SICI:
0887-6924(200105)15:5<772:CWAESC>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
CHRONIC MYELOGENOUS LEUKEMIA; NF-KAPPA-B; TYROSINE KINASE INHIBITOR; CYTOCHROME-C; INDUCED APOPTOSIS; ARSENIC TRIOXIDE; RESISTANCE; ACTIVATION; BCL-X(L); SURVIVAL;
Keywords:
STI-571; As2O3; Bcr-Abl; Bcl-x(L); AKT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Bhalla, KN Univ S Florida, Interdisciplinary Oncol Program, Moffit Canc Ctr, 12902 Magnolia Dr,MRC 3 E,Room 3056, Tampa, FL 33612 USA Univ S Florida 12902 Magnolia Dr,MRC 3 E,Room 3056 Tampa FL USA 33612
Citazione:
M. Porosnicu et al., "Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells", LEUKEMIA, 15(5), 2001, pp. 772-778

Abstract

By inhibiting the tyrosine kinase (TK) activity of Bcr-Abl, STI-571 induces differentiation and apoptosis of HL-60/Bcr-Abl (with ectopic expression of p185 Bcr-Abl) and K562 (containing endogenous expression of p210 Bcr-Abl)but not of the control HL-60 cells. Treatment with arsenic trioxide (As2O3) lowers Bcr-Abl protein levels and induces apoptosis of the Bcr-Abl-positive leukemic blasts (Blood 2000; 95: 1014). Here, we demonstrate that compared to treatment with STI-571 (0.25 to 1.0 muM) or As2O3 (0.5 to 2.0 muM) alone, combined treatment with As2O3 and STI-571 induced significantly more apoptosis of HL60/Bcr-Abl and K562 but not HL-60/neo cells (P < 0.05). Combined treatment with As2O3 and STI-571 also resulted in greater reductions inthe levels of Bcl-x(L), XIAP and Akt, and inhibition of Akt kinase activity. Go-treatment with As2O3 inhibited STI-571-induced hemoglobin, which was associated with the cleavage and downregulation of GATA-1 transcription factor involved in erythroid differentiation. These data demonstrate that a treatment strategy which combines an agent that lowers Bcr-Abl levels, eg As2O3, with an agent that inhibits Bcr-Abl TK activity, eg STI-571, can potently induce apoptosis and differentiation of Bcr-Abl-positive human leukemic cells.

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Documento generato il 30/10/20 alle ore 09:47:57