IOX-101, a novel small molecule, reduces AML cell proliferation by Akt enzyme inhibition

Abstract

Cancer of the blood continues to be a major mortality factor globally. Arylidene compounds are well known for their anticancer effects. Here we describe the biological efficacy of IOX-101, a potential lead-compound of arylidene in acute myeloid leukemia (AML). Initially, molecular docking analysis was performed to check the binding efficacy of the compound with protein kinase B (Akt). The ability of the molecule to inhibit AML proliferation was assessed in THP-1 and Kasumi-6 cells by a standard MTT assay. Hoechst 333258/propidium iodide (PI) staining was carried out to analyze the nuclear damage. Flow cytometry was performed to check the apoptotic and cell cycle changes in THP-1 cells. The effect of IOX-101 on Akt phosphorylation was assessed by Western blot analysis. Molecular docking revealed interaction and binding of IOX-101 with the active site of Akt enzyme. The compound reduced proliferation of both AML cell lines in a dose-responsive way. Nuclear staining and cell cycle results revealed DNA damage by IOX-101 in THP-1 cells, and a significant increase in early and late phase apoptotic cells. A dose-dependent dephosphorylation of Akt (Ser 473) by IOX-101 was observed, which indicated allosteric inhibition of Akt by the compound. Our results showed that the DNA damage-mediated antiproliferative effect of IOX-101 in AML cells was mediated by Akt enzyme inhibition, and that this molecule possesses an effective chemotherapeutic potential against AML.

Keywords

• Akt
• acute myeloid leukemia (AML)
• apoptosis
• cell cycle
• IOX-101