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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4549-4553.
Prepublished online as a Blood First Edition Paper on February 7, 2006; DOI 10.1182/blood-2005-07-2829.
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NEOPLASIA
Brief report
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, and
Antonio Bonati
From the Department of Clinical Sciences, Section of Hemato-Oncology, University of Parma; Department of Dermatology and the Department of Biopathology, Section of Hematology, University of Rome Tor Vergata; Department of Clinical and Experimental Medicine, Section of Hematology and Clinical Immunology, University of Perugia; Department of Internal Medicine and Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome La Sapienza; and the Department of Experimental Oncology, CRS-Regina Elena Cancer Institute, Rome; and the Rome Oncogenomic Center, Italy.
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  Np73 isoforms, thereby failing to elevate the TA/Np73 ratio. Conversely, treatment with PD184352 reduces the level of Np73 and blunts the arsenic-mediated up-regulation of Np73, thus causing an increase in the TA/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.
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