期刊
CANCERS
卷 14, 期 23, 页码 -出版社
MDPI
DOI: 10.3390/cancers14236014
关键词
epigenetics; histone deacetylases (HDACs); lysine demethylases (KMDs); multitargeting; combination therapy; acute myeloid leukemia
类别
资金
- Koc University School of Medicine (KU-SOM budget) [255021011]
- Koc University Research Center for Translational Medicine (KUTTAM)
- Turkish Ministry of Health (TUSEB) [4012]
- UKRI Biotechnology and Biological Sciences Research Council, Norwich Research Park, Biosciences Doctoral Training Partnership [BB/M011216/1]
- Ministry of Education, Science and Technological Development, Republic of Serbia [451-03-9/2021-14/200161]
- Cancer Research UK [C8717/A18245]
- European Research Council (ERC) under the European Union [679479]
- EU COSTAction CM1406 Epigenetic Chemical Biology
- European Research Council (ERC) [679479] Funding Source: European Research Council (ERC)
The newly developed LSD1/HDAC6 dual inhibitor iDual can inhibit the growth of leukemia cells by simultaneously targeting HDAC6 and LSD1, and it can enhance drug-induced apoptosis when used in combination with doxorubicin.
Simple Summary GSK2879552 is a LSD1 inhibitor in clinical development. By structural modification, we obtained an analogue that is a potent and selective dual inhibitor of HDAC6 and LSD1 (IC50 110 and 540 nM, respectively). The dual targeting agent was superior to GSK2879552 in the growth inhibition of two acute myeloid leukemia (AML) cell lines. In combination experiments, the dual inhibitor primed AML cells to apoptosis with a sublethal concentration of doxorubicin. Our data suggest that doxorubicin toxicity can be reduced by parallel inhibition of HDAC6 and LSD1. Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.
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