Abstract |
TP-110, a new proteasome inhibitor, has previously shown potent growth inhibition in various tumor cell lines. In this study, the mechanism of TP-110-induced apoptosis is investigated in a human multiple myeloma cell line. Treatment with TP-110 for 24 h in vitro induced apoptosis in multiple myeloma cell line RPMI8226. Although the expression of Bcl-2, Bcl-xL and Bax was not affected by the treatment of TP-110, cleavage of Bid and release of cytochrome c were enhanced. Interestingly, TP-110 reduced the intrinsic inhibitor of apoptosis proteins (IAPs), cIAP-1 and XIAP, that suppress executioner caspases. The reduction of IAPs was observed not only by TP-110, but also by another proteasome inhibitor, MG-132. These results indicate that proteasome inhibitors reduce the level of IAPs and that the apoptosis induced by TP-110 is correlated with the level of IAPs in leukemia cell lines. Additionally, a reduction of cIAP-1 and XIAP by TP-110 contributes to the sensitization of Fas-mediated apoptosis. Taken together, the alteration of the apoptosis regulatory proteins by a proteasome inhibitor induces apoptosis in tumor cells.
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Authors | Masatomi Iijima, Isao Momose, Daishiro Ikeda |
Journal | Anticancer research
(Anticancer Res)
Vol. 29
Issue 4
Pg. 977-85
(Apr 2009)
ISSN: 0250-7005 [Print] Greece |
PMID | 19414335
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 1-naphthylacetyl-(O-methyl)-tyrosyl-valyl-(O-methyl)-tyrosinal
- Inhibitor of Apoptosis Proteins
- Oligopeptides
- Proteasome Inhibitors
- Cytochromes c
- Poly(ADP-ribose) Polymerases
- Caspases
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Topics |
- Apoptosis
(drug effects)
- Caspases
(metabolism)
- Cytochromes c
(metabolism)
- Down-Regulation
- Humans
- Immunoblotting
- Inhibitor of Apoptosis Proteins
(antagonists & inhibitors, metabolism)
- Multiple Myeloma
(drug therapy, metabolism, pathology)
- Oligopeptides
(pharmacology)
- Poly(ADP-ribose) Polymerases
(metabolism)
- Proteasome Inhibitors
- Tumor Cells, Cultured
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