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J. Chlebowska-Tuz et al.
down with shRNA (Figure 4) exerted cytostatic/cytotoxic effects in HL-60, MOLM14 and KG1 cells and induced dif- ferentiation of HL-60 cells. In contrast to HL-60 cells, thioredoxin knock-down in MOLM14 and KG1 cells was also associated with inhibition of cell growth. Thus, it seems that both thioredoxin and PDI are involved in the survival of these cells, and since SK053 targets both enzymes, the antileukemic activity of this compound can be attributed to its dual selectivity. The findings that SK053 significantly decreases the percentage of CD123+CD34+CD38– leukemia-initiating cells and decreases the clonogenic potential of these cells in the colony formation assay in vitro are particularly important. Leukemia-initiating cells seem to have a pivotal role in the relapse of AML and are considered to be resistant to con- ventional chemotherapy and targeted therapies.26
induces differentiation of AML cells. These observations indicate that PDI is a druggable target for differentiation treatment in AML.
Acknowledgments
The authors thank Dr. Magdalena Winiarska from the Department of Immunology, MUW and Prof. Andrzej Dziembowski from the Institute of Biochemistry and Biophysics PAS for their critical and helpful review of this work as well as Dr. Tomasz Stoklosa from the Department of Immunology, MUW for advice concerning the clonogenic assays. This work was supported by the Polish National Science Center, grant numbers: 2013/10/E/NZ5/00778 (DN), 2014/15/B/ST6/05082 (DP), Foundation for Polish Science (TEAM to DP), Ministry of Science and Higher Education, grant number: IP2011 038971 (DN) and European Commission Horizon 2020 Programme 692180- STREAMH2020-TWINN-2015 (JG).
Altogether, we show that SK053 targets PDI by thiol- dependent interactions, modulates C/EBPα levels and
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