Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells

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.

Antibody-Free Fluorine-Assisted Metabolic Sequencing of RNA N4-Acetylcytidine

“…Moreover, histone deacetylases (HDACs) are highly expressed in various cancers, 50 and recent research has reported that lysine-specific demethylase 1 (LSD1)/ HDAC6 multitargeting inhibitors can induce DOX sensitivity in acute myeloid leukemia cells. 51 Together, these results expand our understanding of the ac 4 C epitranscriptome and hold great potential to overcome the drug resistance of CML.…”

“…Intriguingly, acetylation enhances mRNA stability and translation efficiency and its presence within the wobble position of tRNA promotes translation, 4 which is reminiscent of the activating effect of histone acetylation. Moreover, histone deacetylases (HDACs) are highly expressed in various cancers, and recent research has reported that lysine-specific demethylase 1 (LSD1)/HDAC6 multitargeting inhibitors can induce DOX sensitivity in acute myeloid leukemia cells . Together, these results expand our understanding of the ac 4 C epitranscriptome and hold great potential to overcome the drug resistance of CML.…”

Calcium influx, oxidative stress, and apoptosis induced by TRPV1 in chronic myeloid leukemia cells: Synergistic effects with imatinib

“…However, apoptosis presents itself as a double-edged sword. In fact, it can be the problem and also provide a potential solution, since drugs aimed at activating and/or increasing apoptotic pathways are indeed coveted therapeutic options, especially in the field of leukemia ( Peng et al, 2016 ; Bulut et al, 2022 ). In this scenario, Ca 2+ influx is the master second messenger that influences the proliferation–apoptosis balance: low intracellular levels are required for cell growth stimulation, while its overload is strongly responsible for apoptosis induction ( Shapovalov et al, 2011 ).…”

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

“…at designed a potent and selective dual LSD1/ HDAC6 inhibitor iDual (Table 3, Figure 6), a hydroxamic acid analogue of GSK2879552. 143 iDual effectively inhibited LSD1, HDAC6, and HDAC8 with IC 50 values of 540, 110, and 290 nM, respectively. Furthermore, iDual demonstrated a higher level of growth inhibition in leukemia cell lines THP-1 and MOLM-13 with micromolar IC 50 values than GSK2879552.…”

“…Bulut et. at designed a potent and selective dual LSD1/HDAC6 inhibitor iDual (Table , Figure ), a hydroxamic acid analogue of GSK2879552 . iDual effectively inhibited LSD1, HDAC6, and HDAC8 with IC 50 values of 540, 110, and 290 nM, respectively.…”