Abstract
In recent years there has been an increased focus on the tumorigenesis potential of leukemia initiation cells (LICs) in acute myeloid leukemia (AML). Targeting LICs strategy is hopefully to eradicate leukemia cells in drug development. Autophagy plays a critical role in hematopoietic stem cell life-long maintenance, cancer progression and chemoresistance. p62 (sequestosome 1,SQSTM1) serves as a selective autophagy receptor for degradation of ubiqutinated substrates and loss of p62 impairs leukemia progression in AML mouse model. LP1-106 is a p62-ZZ inhibitor, which was identified through 3D homology modeling and virtual screening molecular docking studies. In this study, we investigated the in vitro and in vivo effects of LP1-106 based on human AML cell lines, primary AML cells and MLL-AF9 AML mouse model. Cytotoxicity and apoptosis assays showed that LP1-106 could significantly inhibit cell proliferation and induce apoptosis. Serial colony-forming unit assays suggested that in vitro treatment with LP1-106 induced a sharp decrease in number of type A colony, which displays higher leukemia-initiation potential. In vivo assay implied that LP1-106 could attenuate myeloid leukemia progression in mice by impairing LICs. Additionaly, we evaluated the safty of LP1-106 in normal human umbilical cord blood-derived mononuclear cells (hUCB-MNCs), which suggested that LP1-106 has no severe impact on nomal hematopoiesis under effective concentration. Our data showed that this small-molecule inhibitor LP1-106 targeting p62-ZZ domain possesses the potential of LICs-surpression. These positive results provide a pharmacological basis for further study of this compound, therefore we plan to continue our research on the leukemia-inhibition mechanism of LP1-106 and its possible clinical application on the treatment of AML incombination with conventional antineoplastic agents.
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