Inhibiting Mcl-1 with an antisense oligonucleotide induces cell death in acute myeloid leukemia cells

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The apoptotic cascade is regulated by multiple families of both pro- and anti-apoptotic proteins. Mcl-1 is a member of the antiapoptotic Bcl-2 family of proteins which is highly expressed in various types of solid and hematological cancers, and has recently been shown to be an important survival factor for hematopoietic stem cells. We have identified and characterized a potent antisense oligonucleotide (ASO) inhibitor of Mcl-1. Transfection of this ASO results in the decreased expression of Mcl-1 protein and the induction of apoptosis in multiple cell types, including HL-60. In this study, we investigated the regulation of Mcl-1 expression and its potential as a therapeutic target in AML cells. We found that Mcl-1 protein level is significantly decreased by MEK inhibition in HL-60 and OCI-AML2 cells suggesting that Mcl-1 expression is regulated through MAPK signaling. Downregulation of Mcl-1 by its antisense oligonucleotide induced cell death accompanied by decreases in mitochondrial membrane potential (MMP), caspase activation and annexin-V positivity, indicating that Mcl-1 is essential for survival in HL-60 cells. By itself, the MEK inhibitor primarily induced G0/G1 cell cycle block. When combined with Mcl-1-ASO, MEK inhibition further decreased Mcl-1 protein level and cell death induced by Mcl-1-ASO was significantly enhanced. These results show that Mcl-1 has the potential to be a good drug target for AML as well as other cancer types. In vivo studies in mouse models of cancer are being performed with this ASO to better understand this potential.