title: Tenovin-6-mediated inhibition of SIRT1/2 induces apoptosis in acute lymphoblastic leukemia (ALL) cells and eliminates ALL stem/progenitor cells.
abstract: BACKGROUND
  Acute lymphoblastic leukemia (ALL) is a heterogeneous group of malignant disorders derived from B- or T-cell lymphoid progenitor cells. ALL often is refractory to or relapses after treatment; thus, novel targeted therapy for ALL is urgently needed. In the present study, we initially found that the level of SIRT1, a class III histone deacetylase, was higher in primary ALL cells from patients than in peripheral blood mononuclear cells from healthy individuals. But it is not clear whether inhibition of SIRT1 by its selective small molecule inhibitor Tenovin-6 is effective against ALL cells.
  
  
  METHODS
  We tested the effect of Tenovin-6 on ALL cell lines (REH and NALM-6) and primary cells from 41 children with ALL and 2 adult patients with ALL. The effects of Tenovin-6 on cell viability were determined by MTS assay; colony-forming assays were determined by soft agar in ALL cell lines and methylcellulose medium in normal bone marrow cells and primary ALL blast cells; cell apoptosis and cell cycling were examined by flow cytometry; the signaling pathway was determined by Western blotting; ALL stem/progenitor cells were seperated by using MACS MicroBead kit.
  
  
  RESULTS
  The results showed that Tenovin-6 treatment activated p53, potently inhibited the growth of pre-B ALL cells and primary ALL cells, and sensitized ALL cells to frontline chemotherapeutic agents etoposide and cytarabine. Tenovin-6 induced apoptosis in REH and NALM-6 cells and primary ALL cells and diminished expression of Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP) in such cells. Furthermore, inhibition of SIRT1 by Tenovin-6 inhibited the Wnt/β-catenin signaling pathway and eliminated ALL stem/progenitor (CD133 + CD19-) cells.
  
  
  CONCLUSIONS
  Our results indicate that Tenovin-6 may be a promising targeted therapy for ALL and clinical trials are warranted to investigate its efficacy in ALL patients.
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China. yanlijin2014@163.com.|Present address: Institute of Tumor Pharmacology, Jinan University College of Pharmacy, 601 West Huangpu Blvd., Guangzhou, 510632, People's Republic of China. yanlijin2014@163.com.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China. Caodapi@163.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510000, People's Republic of China. chenchun69@126.com.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Hematology, Guangdong Provincial People's Hospital, Guangzhou, 510080, People's Republic of China. miyadu@hotmail.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China. jinbei@mail2.sysu.edu.cn.
authors.forename: Bei
authors.initials: B
authors.lastname: Jin
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China. panjx2@mail.sysu.edu.cn.|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China. panjx2@mail.sysu.edu.cn.|Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China. panjx2@mail.sysu.edu.cn.|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, 510060, People's Republic of China. panjx2@mail.sysu.edu.cn.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Pan
mesh_terms: D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016159:Tumor Suppressor Protein p53; C574854:tenovin-6; D056564:Sirtuin 1; D056565:Sirtuin 2