Yuki Okuhashi1, Mai Itoh, Nobuo Nara, Shuji Tohda. 1. Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo 113-8519, Japan.
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. MATERIALS AND 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. CONCLUSION: 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.
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. MATERIALS AND 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. CONCLUSION: 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: Axel Schulenburg; Katharina Blatt; Sabine Cerny-Reiterer; Irina Sadovnik; Harald Herrmann; Brigitte Marian; Thomas W Grunt; Christoph C Zielinski; Peter Valent Journal: J Hematol Oncol Date: 2015-02-25 Impact factor: 17.388
Authors: Nathália G Amado; Danilo Predes; Marcela M Moreno; Igor O Carvalho; Fábio A Mendes; José G Abreu Journal: Int J Mol Sci Date: 2014-07-08 Impact factor: 5.923