The role of CUDC-907, a dual phosphoinositide-3 kinase and histone deacetylase inhibitor, in inhibiting proliferation of adult T-cell leukemia.

ABSTRACT

OBJECTIVES: New effective therapeutic strategies for human T-cell leukemia virus type 1 (HTLV-1)-driven adult T-cell leukemia (ATL) are required because of resistance to chemotherapeutic agents. Here, we aimed to determine the therapeutic efficacy of a dual phosphoinositide 3 kinase (PI3K)/histone deacetylase (HDAC) inhibitor, CUDC-907. METHODS: Cell viability, cell cycle progression, and apoptotic events were examined by WST-8 assay, flow cytometry, and Hoechst 33342 staining. Caspase activity was determined using Calorimetric Caspase Assay kits. Immunoblotting and electrophoretic mobility shift assay were used to assess the intracellular signaling cascades. RESULTS: The combination of PI3K inhibitor BKM120 and HDAC inhibitor LBH589 resulted in a synergistic cytotoxic effect in HTLV-1-infected T cells. CUDC-907 was more efficacious than BKM120 and LBH589. It induced G1 cell cycle arrest with downregulation of cyclin D1/D2, CDK4/6, c-Myc, and phosphorylated retinoblastoma protein expression. Apoptosis was induced via caspase-3/8/9 activation along with downregulation of Bcl-XL , Bcl-2, XIAP, survivin, and cIAP1/2, and upregulation of Bax and Bak. Histone H3 acetylation, H2AX activation, Hsp27 phosphorylation, and Hsp70 and Hsp27 upregulation were observed after treatment. CUDC-907 suppressed Akt, NF-κB, and AP-1 by downregulating phosphorylated and/or total Akt, IKKα/ß, RelA, JunB, and JunD. CONCLUSION: CUDC-907 may be a potential therapeutic agent for ATL.