title: Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells.
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.
authors.affiliation: Centre 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Centre 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Diab
authors.affiliation: Centre 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.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Yu
authors.affiliation: Centre 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.
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.affiliation: Centre 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.
authors.forename: Saiful
authors.initials: S
authors.lastname: Islam
authors.affiliation: Centre 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.
authors.forename: Sunita K C
authors.initials: SK
authors.lastname: Basnet
authors.affiliation: Centre 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.
authors.forename: Hugo
authors.initials: H
authors.lastname: Albrecht
authors.affiliation: Centre 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Milne
authors.affiliation: Centre 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.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D000073840:Copper-Transporting ATPases / Q000037:antagonists & inhibitors*; D003561:Cytarabine / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; D003561:Cytarabine; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases
keywords: Mnk inhibitor; acute myeloid leukemia; combination therapy; cytarabine