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Bulut, Ipek, Lee, Adam, Cevatemre, Buse, Ruzic, Dusan, Belle, Roman, Kawamura, Akane, Gul, Sheraz, Nikolic, Katarina, Ganesan, A. 
ORCID: https://orcid.org/0000-0003-4862-7999 and Acilan, Ceyda
(2022)
Dual LSD1 and HDAC6 inhibition induces doxorubicin sensitivity in acute myeloid leukemia cells.
Cancers, 14 (23).
ISSN 2072-6694
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Abstract
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.
| Item Type: | Article |
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| Additional Information: | Data Availability Statement: All chemistry and biological data are available on request. The agreement numbers for Confirmation of Publication and Licensing Rights for the images created in Biorender.com are: YZ24MZ62HY, AL24MZ7RA3, IU24MZ8A6I, DG24MZK162, KO24N9EINT, GW24MZ5H0L. Funding Information: This research was funded by the following: the Koç University School of Medicine (KUSOM budget 255021011) (I.B., C.A.); the Koç University Research Center for Translational Medicine (KUTTAM), Turkish Ministry of Health (TUSEB) Project No: 4012 (CAA, IB, BC) and the UKRI Biotechnology and Biological Sciences Research Council, Norwich Research Park, Biosciences Doctoral Training Partnership, grant BB/M011216/1 (A.L., A.G.); the Ministry of Education, Science and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade—Faculty of Pharmacy, No: 451-03-9/2021-14/200161 (D.R., K.N.); the Cancer Research UK grant C8717/A18245 (R.B., A.K.); the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme, grant agreement 679479 (A.K.); and the EU COST Action CM1406 Epigenetic Chemical Biology (A.L., D.R., A.K., S.G., K.N. and A.G.). |
| Uncontrolled Keywords: | acute myeloid leukemia,combination therapy,epigenetics,histone deacetylases (hdacs),lysine demethylases (kmds),multitargeting,oncology,cancer research,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2730 |
| Faculty \ School: | Faculty of Science > School of Pharmacy (former - to 2024) Faculty of Science > School of Chemistry, Pharmacy and Pharmacology |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 10 Jan 2025 01:00 |
| Last Modified: | 16 Jan 2025 01:08 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/98138 |
| DOI: | 10.3390/cancers14236014 |
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