Novel Histone Deacetylase Inhibitors Induce Growth Arrest, Apoptosis, and Differentiation in Sarcoma Cancer Stem Cells

Musculoskeletal sarcomas are aggressive malignancies of bone and soft tissues often affecting children and adolescents. Histone deacetylase inhibitors (HDACi) have been proposed to counteract cancer stem cells (CSCs) in solid neoplasms. When tested in human osteosarcoma, rhabdomyosarcoma, and Ewing’s sarcoma stem cells, the new HDACi MC1742 (<b>1</b>) and MC2625 (<b>2</b>) increased acetyl-H3 and acetyl-tubulin levels and inhibited CSC growth by apoptosis induction. At nontoxic doses, <b>1</b> promoted osteogenic differentiation. Further investigation with <b>1</b> will be done in preclinical sarcoma models

Compound MC2776 docked to the KDAC1 protein.

<p><b>(A) in the <i>B</i>. <i>malayi</i> protein and (B) in the <i>H</i>. <i>sapiens</i> protein.</b> MC2776 is shown as yellow stick model along with important residues for ligand binding. (C) shows a close-up view of the zinc-centered square based pyramid, Distances for these are shown in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004026#pntd.0004026.t002" target="_blank">Table 2</a>. (D) and (E) show the rendered surface models of the cartoon representations from (A) and (B).</p

KDAC proteins inferred for the parasitic species within protein families.

<p>Those with the same superscripts (A, B, C) are clustered within the same family. Color codes provide the number of total proteins from each species within an orthologous protein family.</p

Chemical structures of compounds used in parasite screening assays.

<p>Chemical structures of compounds used in parasite screening assays.</p

Expression level of <i>A</i>. <i>suum</i> KDAC1 gene (GS_10652) in different tissues.

<p>Gene expression values are in depth of coverage per million reads (DCPMs). The expression values are averaged across male and female samples.</p

Compound MC2780 docked to the KDAC1 protein.

<p>A) in the <i>B</i>. <i>malayi</i> protein and B) in the <i>H</i>. <i>sapiens</i> protein. MC2780 is shown as grey stick model along with important residues for ligand binding.</p

Additional file 4: of KAT3B-p300 and H3AcK18/H3AcK14 levels are prognostic markers for kidney ccRCC tumor aggressiveness and target of KAT inhibitor CPTH2

Immunostaining of tissue sections from ccRCC tumor and normal tissues with p300, H3AcK18, and H3AcK14 antibodies. Two opposite cases are shown, patient no. 1 with low p300/H3AcK18 vs. high H3AcK14. Patient no. 41, the opposite, high p300/H3AcK18 vs. low H3AcK14. (TIFF 37242 kb