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TP-110, a new proteasome inhibitor, down-regulates IAPs in human multiple myeloma cells.

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.
AuthorsMasatomi Iijima, Isao Momose, Daishiro Ikeda
JournalAnticancer research (Anticancer Res) Vol. 29 Issue 4 Pg. 977-85 (Apr 2009) ISSN: 0250-7005 [Print] Greece
PMID19414335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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