Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells
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Peng Li1, Sarah Diab1, Mingfeng Yu1, Julian Adams1, Saiful Islam1, Sunita K.C. Basnet1, Hugo Albrecht1, Robert Milne1, Shudong Wang1
1Centre for Drug Discovery and Development, Sansom Institute for Health Research, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia
Shudong Wang, email: [email protected]
Keywords: Mnk inhibitor, acute myeloid leukemia, cytarabine, combination therapy
Received: May 03, 2016 Accepted: July 11, 2016 Published: July 23, 2016
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.
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