title: Effects of combination of notch inhibitor plus hedgehog inhibitor or Wnt inhibitor on growth of leukemia cells.
abstract: BACKGROUND
  The Notch inhibitors, γ-secretase inhibitors (GSIs), are promising candidates for molecular targeted therapy against leukemia. However, they show only limited effectiveness. We thought that the efficacy of GSIs might be improved by their combination with Hedgehog inhibitors and Wnt inhibitors because these signaling pathways are also important for the growth of leukemia cells.
  
  
  METHODS
  The effects of the combination of GSI-XXI plus the Hedgehog inhibitor, cyclopamine (Cy), or the Wnt inhibitor, quercetin (Qu), on the in vitro cell growth, colony formation and Notch1 protein expression of three T-cell acute lymphoblastic leukemia (T-ALL) cell lines with NOTCH1 mutations and three acute myeloid leukemia cell lines were examined.
  
  
  RESULTS
  The addition of Cy or Qu to GSI suppressed the growth of DND-41 T-ALL cells additively or synergistically, respectively. Interestingly, Cy treatment and Qu treatment reduced Notch1 protein and its active fragment in DND-41 cells, which suggests a relationship between Notch signaling and Hedgehog or Wnt signaling. The addition of Cy or Qu to GSI promoted the decrease of Notch1 activation and expression.
  
  
  CONCLUSIONS
  The anti-leukemic effects of a GSI could be promoted by its combination with Cy or Qu, in appropriate cases selected by in vitro drug sensitivity test.
authors.affiliation: Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo 113-8519, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okuhashi
authors.forename: Mai
authors.initials: M
authors.lastname: Itoh
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nara
authors.forename: Shuji
authors.initials: S
authors.lastname: Tohda
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003984:Dibenzazepines / Q000494:pharmacology; D004357:Drug Synergism; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D011794:Quercetin / Q000494:pharmacology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D014704:Veratrum Alkaloids / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003984:Dibenzazepines; D053823:Hedgehog Proteins; D051880:Receptors, Notch; D014704:Veratrum Alkaloids; D051153:Wnt Proteins; D011794:Quercetin; C527817:dibenzazepine; C000541:cyclopamine