Proteasome inhibitor 1 enhances paclitaxel-induced apoptosis in human lung adenocarcinoma cell line.
Paclitaxel is a chemotherapeutic drug that induces apoptosis in tumor cells by stabilizing microtubules, prevents normal mitosis, and blocks the cell cycle at the G2/M phase. We have previously reported that the activation of caspase-3 and caspase-8 plays a crucial role in paclitaxel-induced apoptosis. Anti-tumor reagents including paclitaxel, irradiation, and other stimuli activate the transcription factor NF-kappaB, which has the ability to suppress the apoptotic potential of those stimuli. Using a human lung adenocarcinoma cell line (LC-2-AD), we therefore examined whether the inhibition of NF-kappaB activity by proteasome inhibitor 1 (PS1) could become a new adjuvant therapy for cancer. A synergistic effect on apoptosis induction was observed with the combination of more than 0.1 microg/ml paclitaxel and 0.5 microM PS1. An increase in the cell number of apoptotic cells is correlated with the loss of Deltaphim and the activation of caspase-3 and caspase-8. Furthermore, augmented apoptosis is related to NF-kappaB activation. Based on these findings, we propose that the combination of paclitaxel with PS1 could be a new strategy for cancer treatment.
Oyaizu
H
H
First Department of Pathology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
Adachi
Y
Y
Okumura
T
T
Okigaki
M
M
Oyaizu
N
N
Taketani
S
S
Ikebukuro
K
K
Fukuhara
S
S
Ikehara
S
S
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D003546:Cysteine Endopeptidases; D004357:Drug Synergism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D016328:NF-kappa B; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D017239:Paclitaxel