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

Paolo Lunghi, Antonio Costanzo, Luigi Salvatore, Nelida Noguera, Laura Mazzera, Antonio Tabilio, Francesco Lo-Coco, Massimo Levrero, Antonio Bonati

Research output: Contribution to journalArticle

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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 ΔNp73 isoforms, thereby failing to elevate the TA/ΔNp73 ratio. Conversely, treatment with PD184352 reduces the level of ΔNp73 and blunts the arsenic-mediated up-regulation of ΔNp73, thus causing an increase in the TA/ΔNp73 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.

Original languageEnglish
Pages (from-to)4549-4553
Number of pages5
JournalBlood
Volume107
Issue number11
DOIs
Publication statusPublished - Jun 1 2006

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Acute Myeloid Leukemia
Genes
Apoptosis
p53 Genes
Cells
Apoptosis Regulatory Proteins
Arsenic
Protein Isoforms
Up-Regulation
Therapeutics
Gene Expression
arsenic trioxide
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide

ASJC Scopus subject areas

  • Hematology

Cite this

Lunghi, P., Costanzo, A., Salvatore, L., Noguera, N., Mazzera, L., Tabilio, A., ... Bonati, A. (2006). MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis. Blood, 107(11), 4549-4553. https://doi.org/10.1182/blood-2005-07-2829

MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis. / Lunghi, Paolo; Costanzo, Antonio; Salvatore, Luigi; Noguera, Nelida; Mazzera, Laura; Tabilio, Antonio; Lo-Coco, Francesco; Levrero, Massimo; Bonati, Antonio.

In: Blood, Vol. 107, No. 11, 01.06.2006, p. 4549-4553.

Research output: Contribution to journalArticle

Lunghi, P, Costanzo, A, Salvatore, L, Noguera, N, Mazzera, L, Tabilio, A, Lo-Coco, F, Levrero, M & Bonati, A 2006, 'MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis', Blood, vol. 107, no. 11, pp. 4549-4553. https://doi.org/10.1182/blood-2005-07-2829
Lunghi, Paolo ; Costanzo, Antonio ; Salvatore, Luigi ; Noguera, Nelida ; Mazzera, Laura ; Tabilio, Antonio ; Lo-Coco, Francesco ; Levrero, Massimo ; Bonati, Antonio. / MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis. In: Blood. 2006 ; Vol. 107, No. 11. pp. 4549-4553.
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