title: Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells.
abstract: OBJECTIVE
  Colorectal cancers are resistant to conventional chemotherapeutic treatments, including taxanes. gamma-Secretase is a multimeric membrane protein complex responsible for the intramembrane proteolysis of various type I transmembrane proteins, including amyloid beta-precursor protein and Notch. gamma-Secretase inhibitors have attracted increasing interest as anticancer drugs because of their ability to inhibit Notch signaling. However, the therapeutic usefulness of gamma-secretase inhibitors against colorectal cancers remains unclear.
  
  
  METHODS
  The effects of gamma-secretase inhibitors on growth and apoptosis induced by various chemotherapeutic agents in colon cancer cells were evaluated using Hoechst 33342 staining, colony formation assay, and cell cycle analysis. The effect of gamma-secretase inhibitors on taxane-induced mitotic arrest was evaluated using the cyclin B1-associated histone H1 kinase assay and MPM-2 reactivity. The involvement of Notch signaling was evaluated by the silencing of Notch/CBF1 signaling by RNA interference.
  
  
  RESULTS
  gamma-Secretase inhibitors enhanced taxane-induced mitotic arrest and apoptosis of colon cancer cells both in vitro and in vivo, although gamma-secretase inhibitors alone did not affect growth and apoptosis of colon cancer cells. We also showed that this effect by gamma-secretase inhibitors was restricted to taxanes and colon cancer cells. Silencing of Notch/CBF1 signaling failed to affect paclitaxel-induced mitotic arrest and apoptosis.
  
  
  CONCLUSIONS
  These data suggest that gamma-secretase inhibitors could be a new therapeutic modality for overcoming resistance to taxanes in colorectal cancers.
authors.affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakamura
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yanai
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Nagai
authors.forename: Junji
authors.initials: J
authors.lastname: Wada
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Koga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Norihiro
authors.initials: N
authors.lastname: Sato
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Katano
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D043823:Taxoids / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; D043823:Taxoids; C080625:taxane; D014750:Vincristine; D053829:Amyloid Precursor Protein Secretases