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, Hiroshi Handa

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)987-994
Number of pages8
JournalMolecular Pharmacology
Volume73
Issue number3
DOIs
Publication statusPublished - 2008 Mar
Externally publishedYes

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Preclinical Drug Evaluations
Signal Recognition Particle
Type II DNA Topoisomerase
HEK293 Cells
Microspheres
Carrier Proteins
6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one
Poisons
RNA Interference
Gel Chromatography
Interleukin-6
Proteins

ASJC Scopus subject areas

  • Pharmacology

Cite this

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. / Yoshida, Makoto; Kabe, Yasuaki; Wada, Tadashi; Asai, Akira; Handa, Hiroshi.

In: Molecular Pharmacology, Vol. 73, No. 3, 03.2008, p. 987-994.

Research output: Contribution to journalArticle

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