TY  - JOUR
AU  - Bulut, Ipek
AU  - Lee, Adam
AU  - Cevatemre, Buse
AU  - Ružić, Dušan
AU  - Belle, Roman
AU  - Kawamura, Akane
AU  - Gul, Sheraz
AU  - Nikolić, Katarina
AU  - Ganesan, A.
AU  - Acilan, Ceyda
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4340
AB  - 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.
PB  - MDPI
T2  - Cancers
T1  - Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells
VL  - 14
IS  - 23
DO  - 10.3390/cancers14236014
ER  - 

@article{
author = "Bulut, Ipek and Lee, Adam and Cevatemre, Buse and Ružić, Dušan and Belle, Roman and Kawamura, Akane and Gul, Sheraz and Nikolić, Katarina and Ganesan, A. and Acilan, Ceyda",
year = "2022",
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.",
publisher = "MDPI",
journal = "Cancers",
title = "Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells",
volume = "14",
number = "23",
doi = "10.3390/cancers14236014"
}

Bulut, I., Lee, A., Cevatemre, B., Ružić, D., Belle, R., Kawamura, A., Gul, S., Nikolić, K., Ganesan, A.,& Acilan, C.. (2022). Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. in Cancers
MDPI., 14(23).
https://doi.org/10.3390/cancers14236014

Bulut I, Lee A, Cevatemre B, Ružić D, Belle R, Kawamura A, Gul S, Nikolić K, Ganesan A, Acilan C. Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. in Cancers. 2022;14(23).
doi:10.3390/cancers14236014 .

Bulut, Ipek, Lee, Adam, Cevatemre, Buse, Ružić, Dušan, Belle, Roman, Kawamura, Akane, Gul, Sheraz, Nikolić, Katarina, Ganesan, A., Acilan, Ceyda, "Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells" in Cancers, 14, no. 23 (2022),
https://doi.org/10.3390/cancers14236014 . .