Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines
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...
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| Format: | Article |
| Language: | English |
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BMC
2018-08-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-018-4710-1 |
| _version_ | 1818024252452896768 |
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| author | Tomohiro Kozako Paolo Mellini Takeo Ohsugi Akiyoshi Aikawa Yu-ichiro Uchida Shin-ichiro Honda Takayoshi Suzuki |
| author_facet | Tomohiro Kozako Paolo Mellini Takeo Ohsugi Akiyoshi Aikawa Yu-ichiro Uchida Shin-ichiro Honda Takayoshi Suzuki |
| author_sort | Tomohiro Kozako |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T03:57:16Z |
| format | Article |
| id | doaj.art-d44410c5de754805a609bcde9631a189 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-10T03:57:16Z |
| publishDate | 2018-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-d44410c5de754805a609bcde9631a1892022-12-22T02:03:06ZengBMCBMC Cancer1471-24072018-08-0118111010.1186/s12885-018-4710-1Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell linesTomohiro Kozako0Paolo Mellini1Takeo Ohsugi2Akiyoshi Aikawa3Yu-ichiro Uchida4Shin-ichiro Honda5Takayoshi Suzuki6Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka UniversityFaculty of Medicine, Kyoto Prefectural University of MedicineDepartment of Hematology and Immunology, Rakuno Gakuen UniversityDepartment of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka UniversityDepartment of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka UniversityDepartment of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka UniversityFaculty of Medicine, Kyoto Prefectural University of MedicineAbstract 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.http://link.springer.com/article/10.1186/s12885-018-4710-1Human T-cell leukemia virus-1Adult T-cell leukemia/lymphomaSIRT2ApoptosisCaspase-independent cell death |
| spellingShingle | Tomohiro Kozako Paolo Mellini Takeo Ohsugi Akiyoshi Aikawa Yu-ichiro Uchida Shin-ichiro Honda Takayoshi Suzuki Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines BMC Cancer Human T-cell leukemia virus-1 Adult T-cell leukemia/lymphoma SIRT2 Apoptosis Caspase-independent cell death |
| title | Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines |
| title_full | Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines |
| title_fullStr | Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines |
| title_full_unstemmed | Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines |
| title_short | Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines |
| title_sort | novel small molecule sirt2 inhibitors induce cell death in leukemic cell lines |
| topic | Human T-cell leukemia virus-1 Adult T-cell leukemia/lymphoma SIRT2 Apoptosis Caspase-independent cell death |
| url | http://link.springer.com/article/10.1186/s12885-018-4710-1 |
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