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 DeltaNp73 isoforms, thereby failing to 
elevate the TA/DeltaNp73 ratio. Conversely, treatment with PD184352 reduces the 
level of DeltaNp73 and blunts the arsenic-mediated up-regulation of DeltaNp73, 
thus causing an increase in the TA/DeltaNp73 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.