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Identification of Compounds that Correlate with ABCG2 Transporter Function in the National Cancer Institute Anticancer Drug Screen

John F. Deeken, Robert W. Robey, Suneet Shukla, Kenneth Steadman, Arup R. Chakraborty, Balasubramanian Poonkuzhali, Erin G. Schuetz, Susan Holbeck, Suresh V. Ambudkar and Susan E. Bates
Molecular Pharmacology November 2009, 76 (5) 946-956; DOI: https://doi.org/10.1124/mol.109.056192
John F. Deeken
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Robert W. Robey
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Suneet Shukla
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Kenneth Steadman
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Arup R. Chakraborty
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Balasubramanian Poonkuzhali
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Erin G. Schuetz
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Susan Holbeck
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Suresh V. Ambudkar
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Susan E. Bates
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Abstract

ABCG2 is an ATP-binding cassette transporter that counts multiple anticancer compounds among its substrates and is believed to regulate oral bioavailability as well as serve a protective role in the blood-brain barrier, the maternal-fetal barrier, and hematopoietic stem cells. We sought to determine whether novel compounds that interact with the transporter could be identified through analysis of cytotoxicity profiles recorded in the NCI Anticancer Drug Screen database. A flow cytometric assay was used to measure ABCG2 function in the 60 cell lines and generate a molecular profile for COMPARE analysis. This strategy identified >70 compounds with Pearson correlation coefficients (PCCs) >0.4, where reduced drug sensitivity correlated with ABCG2 expression, as well as >120 compounds with PCCs < −0.4, indicating compounds to which ABCG2 expression conferred greater sensitivity. Despite identification of known single nucleotide polymorphisms in the ABCG2 gene in a number of the cell lines, omission of these lines from the COMPARE analysis did not affect PCCs. Available compounds were subjected to validation studies to confirm interaction with the transporter, including flow cytometry, [125I]IAAP binding, and cytotoxicity assays, and interaction was documented in 20 of the 27 compounds studied. Although known substrates of ABCG2 such as mitoxantrone or topotecan were not identified, we characterized three novel substrates—5-hydroxypicolinaldehyde thiosemicarbazone (NSC107392), (E)-N-(1-decylsulfanyl-3-hydroxypropan-2-yl)-3-(6-methyl-2,4-dioxo-1H-pyrimidin-5-yl)prop-2-enamide (NSC265473), and 1,2,3,4,7-pentahydroxy-1,3,4,4a,5,11b-hexahydro[1,3]dioxolo[4,5-j]phenanthridin-6(2H)-one [NSC349156 (pancratistatin)]—and four compounds that inhibited transporter function—2-[methyl(2-pyridin-2-ylethyl)-amino]fluoren-9-one hydroiodide (NSC24048), 5-amino-6-(7-amino-5,8-dihydro-6-methoxy-5,8-dioxo-2-quinolinyl)-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-methyl-2-pyridinecarboxylic acid, methyl ester (NSC45384), (17β)-2,4-dibromo-estra-1,3,5(10)-triene-3,17-diol (NSC103054), and methyl N-(pyridine-4-carbonylamino)carbamodithioate (NSC636795). In summary, COMPARE analysis of the NCI drug screen database using the ABCG2 functional profile was able to identify novel substrates and transporter-interacting compounds.

  • ABC, ATP-binding cassette
  • SN-38, 7-ethyl-10-hydroxycamptothecin glucuronide
  • FTC, Fumitremorgin C
  • GF 120918, elacridar
  • XR9576, tariquidar
  • VX-710, biricodar
  • SNP, single nucleotide polymorphism
  • NCI-ADS, National Cancer Institute Developmental Therapeutics Program's Anticancer Drug Screen
  • DTP, Developmental Therapeutics Program
  • P-gp, P-glycoprotein
  • MRP1, multidrug resistance-associated protein 1
  • PhA, pheophorbide A
  • IAAP, iodoarylazidoprazosin
  • HEK, human embryonic kidney
  • PCC, Pearson correlation coefficient
  • NSC103054, (17β)-2,4-dibromo-estra-1,3,5(10)-triene-3,17-diol
  • NSC107392, 5-hydroxypicolinaldehyde thiosemicarbazone
  • NSC114609, (6E)-6-[[(1,3-dihydroxy-2-methylpropan-2-yl)amino]methylidene]-2,4-diiodocyclohexa-2,4-dien-1-one
  • NSC153330, 2-methyl-5,6,7,8-tetrahydro-3H-[1]benzothiolo[2,3-d]pyrimidin-4-one
  • NSC174939, 1-N′,3-N′-bis(benzenecarbonothioyl)-1-N′,3-N′-dimethylpropanedihydrazide
  • NSC24048, 2-[methyl(2-pyridin-2-ylethyl)amino]fluoren-9-one hydroiodide
  • NSC265473/NSC305458, (E)-N-(1-decylsulfanyl-3-hydroxypropan-2-yl)-3-(6-methyl-2,4-dioxo-1H-pyrimidin-5-yl)prop-2-enamide
  • NSC297093, 2,2-dimethyl-5-[(5-nitrothiophen-2-yl)methylidene]-1,3-dioxane-4,6-dione
  • NSC349156, 1,2,3,4,7-pentahydroxy-1,3,4,4a,5,11b-hexahydro[1,3]dioxolo[4,5-j]phenanthridin-6(2H)-one (pancratistatin)
  • NSC382054, 6-ethyl-5-(3-oxo-2-phenyl-1H-benzotriazol-3-ium-5-yl)pyrimidine-2,4-diamine
  • NSC45384, 5-amino-6-(7-amino-5,8-dihydro-6-methoxy-5,8-dioxo-2-quinolinyl)-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-methyl-2-pyridinecarboxylic acid, methyl ester
  • NSC608001, 4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]benzoic acid
  • NSC620303, N′-[(E)-(3-iodo-5-nitro-6-oxocyclohexa-2,4-dien-1-ylidene)methyl]-3-nitrobenzenesulfonohydrazide
  • NSC620515, 2-chloro-8-hydroxy-6-methoxy-7-methylnaphthalene-1,4-dione
  • NSC623636, 2-bromo-5-methoxycyclohexa-2,5-diene-1,4-dione
  • NSC625546, [4-(2,4-dihydroxybenzoyl)-2,5-bis(4-hydroxyphenyl)oxolan-3-yl]-(2,4-dihydroxy-phenyl)methanone
  • NSC636795, methyl N-(pyridine-4-carbonylamino)carbamodithioate
  • NSC651644, 4-amino-N-[3-chloro-2-(3-nitrophenyl)-4-oxoazetidin-1-yl]benzamide
  • NSC686342, 2-[3-cyano-5,5-dimethyl-4-[(E)-2-pyridin-4-ylethenyl]furan-2-ylidene]propanedinitrile
  • NSC691417, ethyl (1E)-N-[5-cyano-4-(3,4-dimethoxyphenyl)-1,3-diphenyl-4H-pyrano[2,3-c]pyrazol-6-yl]methanimidate
  • NSC722812, 5-[(5-cyano-2-hydroxy-6-morpholin-4-yl-4-oxo-1H-pyridin-3-yl)-(2,6-dichlorophenyl)methyl]-6-hydroxy-2-morpholin-4-yl-4-oxo-1H-pyridine-3-carbonitril.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported in part by the Intramural Research Program of the National Institutes of Health National Cancer Institute; by the National Institutes of Health National Institute of General Medical Sciences [Grants U01-GM61374, U01-GM61393], by the National Institutes of Health National Cancer Institute [Grant P30-CA21765]; and by the American Lebanese Syrian Associated Charities.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.056192

  • ABBREVIATIONS:

    • Received March 17, 2009.
    • Accepted July 23, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Identification of Compounds that Correlate with ABCG2 Transporter Function in the National Cancer Institute Anticancer Drug Screen

John F. Deeken, Robert W. Robey, Suneet Shukla, Kenneth Steadman, Arup R. Chakraborty, Balasubramanian Poonkuzhali, Erin G. Schuetz, Susan Holbeck, Suresh V. Ambudkar and Susan E. Bates
Molecular Pharmacology November 1, 2009, 76 (5) 946-956; DOI: https://doi.org/10.1124/mol.109.056192

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Identification of Compounds that Correlate with ABCG2 Transporter Function in the National Cancer Institute Anticancer Drug Screen

John F. Deeken, Robert W. Robey, Suneet Shukla, Kenneth Steadman, Arup R. Chakraborty, Balasubramanian Poonkuzhali, Erin G. Schuetz, Susan Holbeck, Suresh V. Ambudkar and Susan E. Bates
Molecular Pharmacology November 1, 2009, 76 (5) 946-956; DOI: https://doi.org/10.1124/mol.109.056192
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