RRC ID 54125
Author Kozako T, Mellini P, Ohsugi T, Aikawa A, Uchida YI, Honda SI, Suzuki T.
Title Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines.
Journal BMC Cancer
Abstract BACKGROUND:Sirtuin 2 (SIRT2) is a member of the sirtuin family, nicotinamide adenine dinucleotide+-dependent deacylases, which participates in modulation of cell cycle control, neurodegeneration, and tumorigenesis. SIRT2 expression increases in acute myeloid leukemia blasts. Downregulation of SIRT2 using siRNA causes apoptosis of HeLa cells. Therefore, selective inhibitors of SIRT2 are candidate therapeutic agents for cancer. Adult T-cell leukemia/lymphoma (ATL) is a T-cell malignancy that has a poor prognosis and develops after long-term infection with human T-cell leukemia virus (HTLV)-1. Sirtuin 1 inhibition has been shown to induce apoptosis and autophagy in HTLV-1-infected cell lines, whereas the effects of SIRT2 inhibition alone have not been elucidated.
METHODS:We assessed the efficacy of our small molecule selective SIRT2 inhibitors NCO-90/141 to induce leukemic cell death. Cell viability was examined using the cell proliferation reagent Cell Count Reagent SF. Apoptotic cells were detected by annexin V-FITC and terminal deoxynucleotidyl transferase dUTP nick end labeling assays by flow cytometry. Caspase activity was detected using an APOPCYTO Intracellular Caspase Activity Detection Kit. The presence of autophagic vacuoles was assessed using a Cyto-ID Autophagy Detection Kit.
RESULTS:Our novel small molecule SIRT2-specific inhibitors NCO-90/141 inhibited cell growth of leukemic cell lines including HTLV-1-transformed T-cells. NCO-90/141 induced apoptosis via caspase activation and mitochondrial superoxide generation in leukemic cell lines. However, a caspase inhibitor did not prevent this caspase-associated cell death. Interestingly, NCO-90/141 increased the LC3-II level together with autophagosome accumulation, indicating autophagic cell death. Thus, NCO-90/141 simultaneously caused apoptosis and autophagy.
CONCLUSIONS:These results suggest that NCO-90/141 are highly effective against leukemic cells in caspase-dependent or -independent manners via autophagy, and they may have a novel therapeutic potential for treatment of leukemias including ATL.
Volume 18(1)
Pages 791
Published 2018-8-6
DOI 10.1186/s12885-018-4710-1
PII 10.1186/s12885-018-4710-1
PMID 30081901
PMC PMC6091197
MeSH Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Autophagy / drug effects* Caspases / metabolism Cell Proliferation / drug effects HL-60 Cells Histone Deacetylase Inhibitors / pharmacology* Humans Jurkat Cells Leukemia / drug therapy* Leukemia / enzymology Leukemia / pathology Microtubule-Associated Proteins / metabolism Mitochondria / drug effects Mitochondria / enzymology Mitochondria / pathology Signal Transduction / drug effects Sirtuin 2 / antagonists & inhibitors* Sirtuin 2 / metabolism Superoxides / metabolism
IF 2.933
Times Cited 11
Human and Animal Cells HL60(RCB0041) KU812-F(RCB3053)