Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line.
5-fluorouracil (5-FU) is used for the treatment of stomach and colon cancer, but many tumors are resistant to this chemotherapeutic agent. 5-FU induces apoptosis of several cancer cell lines, while some chemotherapeutic agents are known to activate the transcriptional factor NF-kappaB, which strongly suppresses apoptosis in vitro. In the present study, we investigated the relationship between activation of NF-kappaB and chemoresistance to 5-FU in human stomach cancer cell lines, NUGC3 (5-FU sensitive) and NUGC3/5FU/L (5-FU resistant). Treatment with 5-FU for 9-12 h caused activation of inducible NF-kappaB in NUGC3/5FU/L cells but not in NUGC3 cells. 5-FU also resulted in an increase in the number of TUNEL-positive cells and enhanced caspase-3 activity 3- to 5-fold in NUGC3 cells but not NUGC3/5FU/L cells. Moreover we also demonstrated that the inhibition of inducible NF-kappaB activation by using a NF-kappaB decoy could induce apoptosis and reduce chemoresistance against 5-FU. Our results suggest that 5-FU chemoresistance can be overcome by inhibition of inducible NF-kappaB activation, and that the use of the NF-kappaB decoy combined with 5-FU treatment is a new molecular and gene therapeutic strategy aimed at treatment of human stomach cancers resistant to 5-FU.
Uetsuka
Hirokazu
H
Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikatacho, Okayama 700-8558, Japan.
Haisa
Minoru
M
Kimura
Masashi
M
Gunduz
Mehmet
M
Kaneda
Yasufumi
Y
Ohkawa
Takaomi
T
Takaoka
Munenori
M
Murata
Toshihiro
T
Nobuhisa
Tetsuji
T
Yamatsuji
Tomoki
T
Matsuoka
Junji
J
Tanaka
Noriaki
N
Naomoto
Yoshio
Y
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000819:agonists* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D005472:Fluorouracil / Q000819:agonists* / Q000633:toxicity; D006801:Humans; D016328:NF-kappa B / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D016328:NF-kappa B; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005472:Fluorouracil