Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells.
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.
Akiyoshi
Takashi
T
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nakamura
Masafumi
M
Yanai
Kosuke
K
Nagai
Shuntaro
S
Wada
Junji
J
Koga
Kenichiro
K
Nakashima
Hiroshi
H
Sato
Norihiro
N
Tanaka
Masao
M
Katano
Mitsuo
M
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
D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; D043823:Taxoids; C080625:taxane; D014750:Vincristine; D053829:Amyloid Precursor Protein Secretases