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Molecular Pharmacology

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Research ArticleArticle

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
Molecular Pharmacology March 2008, 73 (3) 987-994; DOI: https://doi.org/10.1124/mol.107.043307
Makoto Yoshida
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Yasuaki Kabe
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Tadashi Wada
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Akira Asai
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Hiroshi Handa
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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.

Footnotes

  • This study was supported by Special Coordination Funds for Promoting Science and Technology from the Japan Science and Technology Agency and by 21st Century COE program and Global COE program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This work was also supported by a grant for research and development projects in Cooperation with Academic Institution from the New Energy and Industrial Technology Development Organization.

  • ABBREVIATIONS: topo, topoisomerase; SRP, signal recognition particle; DMF, N,N-dimethylformamide; IL-6, interleukin-6; NE, nuclear extract; buffer E, Tris-HCl, NaCl, MgCl2, CaCl2, EDTA, and glycerol; NP-40, Nonidet P-40; PBS, phosphate-buffered saline; ER, endoplasmic reticulum; SN-38, 7-ethyl-10-hydroxycamptothecin; VP-16, 4′-demethylepipodophyllotoxin 9-(4,6-O-(R)-ethylidene-β-d-glucopyranoside).

    • Received November 7, 2007.
    • Accepted December 18, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (3)
Molecular Pharmacology
Vol. 73, Issue 3
1 Mar 2008
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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
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Research ArticleArticle

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
Molecular Pharmacology March 1, 2008, 73 (3) 987-994; DOI: https://doi.org/10.1124/mol.107.043307

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Research ArticleArticle

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
Molecular Pharmacology March 1, 2008, 73 (3) 987-994; DOI: https://doi.org/10.1124/mol.107.043307
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