title: Inhibition of P-TEFb by DRB suppresses SIRT1/CK2α pathway and enhances radiosensitivity of human cancer cells.
abstract: BACKGROUND
  Positive transcription elongation factor-b (P-TEFb) is a complex containing CDK9 and a cyclin (T1, T2 or K). The effect of inhibition of P-TEFb by 5,6-dichloro-l-β-D-ribofuranosyl benzimidazole (DRB) on cell radiosensitivity and the underlying mechanisms were investigated.
  
  
  METHODS
  Six human cancer cell lines were subjected to (3)H-uridine incorporation, cell viability and clonogenic cell survival assays; cell-cycle redistribution and apoptosis assay; western blots and nuclear 53BP1 foci analysis after exposing the cells to DRB with/without γ-radiation.
  
  
  RESULTS
  DRB suppressed colony formation and enhanced radiosensitivity of all cell lines. DRB caused a further increase in radiation-induced apoptosis and cell-cycle redistribution depending on p53 status. DRB prolonged the presence of radiation-induced nuclear p53 binding protein-1 (53BP1) foci and suppressed the expression of sirtuin-1 (SIRT1) and casein kinase 2-alpha (CK2α), suggesting an inhibition of DNA repair processes.
  
  
  CONCLUSIONS
  Our findings indicate that DRB has the potential to increase the efficacy of radiotherapy and warrants further investigation using in vivo tumor models.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Casey L
authors.initials: CL
authors.lastname: Johnson
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: David P
authors.initials: DP
authors.lastname: Molkentine
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Molkentine
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Rabin
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Mason
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Luka
authors.initials: L
authors.lastname: Milas
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A. uraju@mdanderson.org.
authors.forename: Uma
authors.initials: U
authors.lastname: Raju
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011838:Radiation-Sensitizing Agents; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D004004:Dichlororibofuranosylbenzimidazole; D042925:Positive Transcriptional Elongation Factor B; D047390:Casein Kinase II; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: CDK9; CK2α; DNA repair; DRB; RNA polymerase II; SIRT1; radiosensitivity