MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on December 18, 2007; DOI: 10.1124/mol.107.043307

0026-895X/08/7303-987-994$20.00
Mol Pharmacol 73:987-994, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.107.043307v1
73/3/987    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yoshida, M.
Right arrow Articles by Handa, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yoshida, M.
Right arrow Articles by Handa, H.

A New Mechanism of 6-((2-(Dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one Dihydrochloride (TAS-103) Action Discovered by Target Screening with Drug-Immobilized Affinity Beads

Makoto Yoshida, Yasuaki Kabe, Tadashi Wada, Akira Asai, and Hiroshi Handa

Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (M.Y.,Y.K.,T.W.,H.H.); Integrated Research Institute Graduate school of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (T.W.,H.H.); and Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (A.A.)

6-((2-(Dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)-quinolin-7-one dihydrochloride (TAS-103) is a quinoline derivative that displays antitumor activity in murine and human tumor models. TAS-103 has been reported to be a potent topoisomerase II poison. However, other studies have indicated that cellular susceptibility to TAS-103 is not correlated with topoisomerase II expression. Because the direct target of TAS-103 remained unclear, we searched for a TAS-103 binding protein using high-performance affinity latex beads. We obtained a component of the signal recognition particle (SRP) as a TAS-103 binding protein. This component is a 54-kDa subunit (SRP54) of SRP, which mediates the proper delivery of secretory proteins in cells. We fractioned 293T cell lysates using gel-filtration chromatography and performed a coimmunoprecipitation assay using 293T cells expressing FLAG-tagged SRP54. The results revealed that TAS-103 disrupts SRP complex formation and reduces the amount of SRP14 and SRP19. TAS-103 treatment and RNAi-mediated knockdown of SRP54 or SRP14 promoted accumulation of the exogenously expressed chimeric protein interleukin-6-FLAG inside cells. In conclusion, we identified signal recognition particle as a target of TAS-103 by using affinity latex beads. This provides new insights into the mechanism underlying the effects of chemotherapies comprising TAS-103 and demonstrates the usefulness of the affinity beads.

Received November 7, 2007; accepted December 18, 2007

Address correspondence to: Dr. Hiroshi Handa, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8501, Japan. E-mail: hhanda{at}bio.titech.ac.jp






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics