We found that MEK1 inhibitor PD184352 strikingly increased apoptosis induced by arsenic trioxide (ATO) in 21 of 25 patients with primary acute myelogenous leukemia (AML). Isobologram analysis confirmed the synergistic (13 of 25 patients) or additive (8 of 25 patients) nature of this interaction. Moreover, we demonstrated that the p53-related gene p73 is a molecular target of the combined treatment in AML blasts. Indeed, ATO modulates the expression of the p73 gene by inducing the proapoptotic and antiproliferative TAp73 and the antiapoptotic and proproliferative Delta Np73 isoforms, thereby failing to elevate the TA/Delta Np73 ratio. Conversely, treatment with PD184352 reduces the level of Delta Np73 and blunts the arsenic-mediated up-regulation of Delta Np73, thus causing an increase in the TA/Delta Np73 ratio of dual-treated cells. High doses of ATO induced p53 accumulation in 11 of 21 patients. Combined treatment resulted in the induction of the proapoptotic p53/p73 target gene p53AIP1 (p53-regulated apoptosis-inducing protein 1) and greatly enhanced the apoptosis of treated cells.

Lunghi, P., Costanzo, A., Salvatore, L., Noguera, N., Mazzera, L., Tabilio, A., et al. (2006). MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis. BLOOD, 107(11), 4549-4553 [10.1182/blood-2005-07-2829].

MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis

COSTANZO, ANTONIO;Noguera, N;LO COCO, FRANCESCO;
2006

Abstract

We found that MEK1 inhibitor PD184352 strikingly increased apoptosis induced by arsenic trioxide (ATO) in 21 of 25 patients with primary acute myelogenous leukemia (AML). Isobologram analysis confirmed the synergistic (13 of 25 patients) or additive (8 of 25 patients) nature of this interaction. Moreover, we demonstrated that the p53-related gene p73 is a molecular target of the combined treatment in AML blasts. Indeed, ATO modulates the expression of the p73 gene by inducing the proapoptotic and antiproliferative TAp73 and the antiapoptotic and proproliferative Delta Np73 isoforms, thereby failing to elevate the TA/Delta Np73 ratio. Conversely, treatment with PD184352 reduces the level of Delta Np73 and blunts the arsenic-mediated up-regulation of Delta Np73, thus causing an increase in the TA/Delta Np73 ratio of dual-treated cells. High doses of ATO induced p53 accumulation in 11 of 21 patients. Combined treatment resulted in the induction of the proapoptotic p53/p73 target gene p53AIP1 (p53-regulated apoptosis-inducing protein 1) and greatly enhanced the apoptosis of treated cells.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/35 - Malattie Cutanee e Veneree
English
Con Impact Factor ISI
ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE MYELOID-LEUKEMIA; P53 GENE-MUTATIONS; DNA-DAMAGE; P53-DEPENDENT APOPTOSIS; IN-VIVO; C-ABL; P73; DELTA-NP73; CELLS
5
Lunghi, P., Costanzo, A., Salvatore, L., Noguera, N., Mazzera, L., Tabilio, A., et al. (2006). MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis. BLOOD, 107(11), 4549-4553 [10.1182/blood-2005-07-2829].
Lunghi, P; Costanzo, A; Salvatore, L; Noguera, N; Mazzera, L; Tabilio, A; LO COCO, F; Levrero, M; Bonati, A
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/34285
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