A new proteasome inhibitor, TP-110, induces apoptosis in human prostate cancer PC-3 cells.
Proteasome inhibitors are useful in the treatment of cancer. Recently, we found a new proteasome inhibitor, TP-110, derived from tyropeptin A produced by Kitasatospora sp. Here we report that TP-110 induces apoptosis in human prostate cancer PC-3 cells. TP-110 showed strong cytotoxicity to PC-3 cells (IC(50)=0.05 muM). It increased the number of cells in the G(2)-M phase and increased the accumulated amounts of the p21 and p27 proteins, which are negative regulators of cell cycle progression. Furthermore, it induced apoptosis along with chromatin condensation and DNA fragmentation in PC-3 cells, and TP-110-induced apoptosis appeared to be associated with caspase activation. Additionally, TP-110 inhibited not only the degradation of IkappaB and the nuclear translocation of nuclear factor-kappaB (NF-kappaB), but also the DNA binding activity of NF-kappaB. These results indicate that TP-110 shows a strong growth inhibition and apoptosis in PC-3 cells.
Momose
Isao
I
Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Numazu, Shizuoka, Japan. imomose@bikaken.or.jp
Iijima
Masatomi
M
Kawada
Manabu
M
Ikeda
Daishiro
D
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D005456:Fluorescent Dyes; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D061988:Proteasome Inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction
C506903:1-naphthylacetyl-(O-methyl)-tyrosyl-valyl-(O-methyl)-tyrosinal; D000903:Antibiotics, Antineoplastic; D001562:Benzimidazoles; D005456:Fluorescent Dyes; D016328:NF-kappa B; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C017807:bisbenzimide ethoxide trihydrochloride