Abstract
Cytarabine (Ara-C) is a first line clinical therapeutic agent for treatment of acute myeloid leukemia (AML). However, this therapy is limited due to high rate of resistance and relapse. Recent research has revealed that the poor prognosis and resistance to Ara-C in AML were associated with its abnormally activated MAPK pathways. In this study, we showed a strong synergistic effect of Ara-C with either our Mnk inhibitor (MNKI-8e) or short hairpin RNA (shRNA) mediated knockdown of Mnks in MV4-11 AML cells. We investigated the underlying mechanisms for this synergism. We showed that both MNKI-8e and Mnk shRNAs enhanced the ability of Ara-C to induce apoptosis. We found that Ara-C increased the phosphorylation of Erk1/2, p38 and eIF4E, which correlated with an enhanced level of anti-apoptotic Mcl-1 protein. Inhibition of Mnk activity suppressed the Ara-C-induced MAPK activity, and thus enhanced apoptosis in MV4-11 cells. Taken together, our study suggests that MAPK-Mnk-eIF4E pathway plays a critical role in Ara-C-treated MV4-11 cells and targeting Mnk may be a promising therapeutic strategy for sensitizing leukemic cells to Ara-C therapy.
Highlights
The current treatments for acute myeloid leukemia (AML) have major limitations, and the need for novel therapies is urgent and of high clinical importance [1, 2]
We investigated the underlying mechanisms for this synergism. We showed that both MNKI-8e and MAPK-interacting kinases (Mnks) short hairpin RNA (shRNA) enhanced the ability of Ara-C to induce apoptosis
The anti-cancer activity of MNKI-8e was firstly assessed against five human AML cell lines, i.e. MV411, Kasumi-1, PL-21, KG-1 and U937, which represent different French–American–British (FAB) subtypes
Summary
The current treatments for acute myeloid leukemia (AML) have major limitations, and the need for novel therapies is urgent and of high clinical importance [1, 2]. The typical treatment strategy for AML, referred to as 7+3 therapy, involves a regimen of cytarabine (Ara-C) followed by daunorubicin or idarubicin [3]. These chemotherapeutic treatments have high relapse rates (about 70%) and are associated with resistance and toxicity, leading to dismal long term survival rates and poor quality of life for the patients with AML [4]. It has recently been recognized that the activated mitogen-activated protein kinase (MAPK) pathways play important roles in the poor prognosis of AML and its development of resistance to Ara-C treatment [58]. Erk1/2 and p38 are key kinases of the MAPK pathways and activate
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