title: Inhibition of telomerase using BIBR1532 enhances doxorubicin-induced apoptosis in pre-B acute lymphoblastic leukemia cells.
abstract: OBJECTIVE
  Interest into targeting telomerase in cancer has increased by the recent disclosure that elevated telomerase activity is associated with disease recurrence and poor outcome in cancers. In addition, cellular acquisition of unlimited replicative potential, which is closely related to the maintenance of telomeres mostly via the reactivation of telomerase, has been shown to confer loss of sensitivity to a wide range of anti-neoplastic agents.
  
  
  METHODS
  To evaluate whether telomerase inhibition using non-nucleosidic inhibitor of telomerase BIBR1532 could enhance cytotoxic effect of doxorubicin in acute lymphoblastic leukemia, Nalm-6 pre-B ALL cells were subjected to combination treatment and subsequent cell viability, growth kinetics, caspase-3 activity, and transcriptional alteration of p73, p21, FOXO3a, c-Myc, hTERT, and other apoptosis-related target genes were investigated.
  
  
  RESULTS
  Combination of BIBR1532 with doxorubicin produced a synergistic anticancer effect probably through induction of p73. Transcription factor p73 not only suppressed the proliferative capacity of the cells through induction of p21-mediated G1 arrest, but also down-regulated the mRNA level of hTERT and c-Myc. Our results also report that BIBR1532 induced a caspase-dependent apoptosis, at least partially, through heightened ROS levels, and noteworthy enhanced the pro-oxidant property of doxorubicin. In harmony, transcriptional repression of survivin could be a probable underlying mechanism for the induction of apoptosis through shifting the ratio of death promoters to death repressors via alteration of Bax and Bcl2 expression.
  
  
  CONCLUSIONS
  Overall, it seems that combination of BIBR1532 and doxorubicin could be a novel therapeutic strategy for acute lymphoblastic leukemia that may be clinically accessible in the near future.
authors.affiliation: a Department of Hematology and Blood Banking, School of Allied Medical Sciences , Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors.forename: Davood
authors.initials: D
authors.lastname: Bashash
authors.affiliation: a Department of Hematology and Blood Banking, School of Allied Medical Sciences , Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors.forename: Mohadeseh
authors.initials: M
authors.lastname: Zareii
authors.affiliation: a Department of Hematology and Blood Banking, School of Allied Medical Sciences , Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors.forename: Ava
authors.initials: A
authors.lastname: Safaroghli-Azar
authors.affiliation: b Department of Medical Genetics, Faculty of Medicine , Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors.forename: Mir Davood
authors.initials: MD
authors.lastname: Omrani
authors.affiliation: c Hematology, Oncology and Stem Cell Transplantation Research Center , Tehran University of Medical Sciences , Tehran , Iran.
authors.forename: Seyed H
authors.initials: SH
authors.lastname: Ghaffari
mesh_terms: D062365:Aminobenzoates / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D062365:Aminobenzoates; D000903:Antibiotics, Antineoplastic; C458523:BIBR 1532; D009281:Naphthalenes; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D019098:Telomerase; D053148:Caspase 3
keywords: BIBR1532; Nalm-6 cells; Pre-B ALL; doxorubicin; telomerase