Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells
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 IC<sub>50</sub> values of 540, 110,...
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MDPI AG
2022-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/23/6014 |
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| author | Ipek Bulut Adam Lee Buse Cevatemre Dusan Ruzic Roman Belle Akane Kawamura Sheraz Gul Katarina Nikolic A. Ganesan Ceyda Acilan |
| author_facet | Ipek Bulut Adam Lee Buse Cevatemre Dusan Ruzic Roman Belle Akane Kawamura Sheraz Gul Katarina Nikolic A. Ganesan Ceyda Acilan |
| author_sort | Ipek Bulut |
| collection | DOAJ |
| description | 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 IC<sub>50</sub> 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 IC<sub>50</sub> 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. |
| first_indexed | 2024-03-09T17:51:43Z |
| format | Article |
| id | doaj.art-ce788b04174646f39364049020d1cf5b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T17:51:43Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ce788b04174646f39364049020d1cf5b2023-11-24T10:42:22ZengMDPI AGCancers2072-66942022-12-011423601410.3390/cancers14236014Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia CellsIpek Bulut0Adam Lee1Buse Cevatemre2Dusan Ruzic3Roman Belle4Akane Kawamura5Sheraz Gul6Katarina Nikolic7A. Ganesan8Ceyda Acilan9Graduate School of Health Sciences, Koc University, Sariyer 34450, TurkeySchool of Pharmacy, University of East Anglia, Norwich NR4 7TJ, UKResearch Center for Translational Medicine (KUTTAM), Koc University, Sariyer 34450, TurkeyDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, SerbiaChemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UKChemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UKFraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, GermanyDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, SerbiaSchool of Pharmacy, University of East Anglia, Norwich NR4 7TJ, UKResearch Center for Translational Medicine (KUTTAM), Koc University, Sariyer 34450, TurkeyDefects 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 IC<sub>50</sub> 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 IC<sub>50</sub> 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.https://www.mdpi.com/2072-6694/14/23/6014epigeneticshistone deacetylases (HDACs)lysine demethylases (KMDs)multitargetingcombination therapyacute myeloid leukemia |
| spellingShingle | Ipek Bulut Adam Lee Buse Cevatemre Dusan Ruzic Roman Belle Akane Kawamura Sheraz Gul Katarina Nikolic A. Ganesan Ceyda Acilan Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells Cancers epigenetics histone deacetylases (HDACs) lysine demethylases (KMDs) multitargeting combination therapy acute myeloid leukemia |
| title | Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells |
| title_full | Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells |
| title_fullStr | Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells |
| title_full_unstemmed | Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells |
| title_short | Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells |
| title_sort | dual lsd1 and hdac6 inhibition induces doxorubicin sensitivity in acute myeloid leukemia cells |
| topic | epigenetics histone deacetylases (HDACs) lysine demethylases (KMDs) multitargeting combination therapy acute myeloid leukemia |
| url | https://www.mdpi.com/2072-6694/14/23/6014 |
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