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Molecular Pharmacology

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Research ArticleArticle

Functional Loss of the Reduced Folate Carrier Enhances the Antitumor Activities of Novel Antifolates with Selective Uptake by the Proton-Coupled Folate Transporter

Sita Kugel Desmoulin, Lei Wang, Lisa Polin, Kathryn White, Juiwanna Kushner, Mark Stout, Zhanjun Hou, Christina Cherian, Aleem Gangjee and Larry H. Matherly
Molecular Pharmacology October 2012, 82 (4) 591-600; DOI: https://doi.org/10.1124/mol.112.079004
Sita Kugel Desmoulin
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Lei Wang
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Lisa Polin
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Kathryn White
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Juiwanna Kushner
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Mark Stout
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Zhanjun Hou
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Christina Cherian
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Aleem Gangjee
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Larry H. Matherly
Graduate Program in Cancer Biology (S.K.D., L.H.M.) and Departments of Oncology (S.K.D., L.P., K.W., J.K., Z.H., C.C., L.H.M.) and Pharmacology (L.H.M.), Wayne State University School of Medicine, Detroit, Michigan; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan (L.P., Z.H., C.C., L.H.M.); Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan (M.S.); and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Science, Duquesne University, Pittsburgh, Pennsylvania (L.W., A.G.)
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Abstract

Uptake of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates with four or three bridge carbons [compound 1 (C1) and compound 2 (C2), respectively] into solid tumors by the proton-coupled folate transporter (PCFT) represents a novel therapeutic strategy that harnesses the acidic tumor microenvironment. Although these compounds are not substrates for the reduced folate carrier (RFC), the major facilitative folate transporter, RFC expression may alter drug efficacies by affecting cellular tetrahydrofolate (THF) cofactor pools that can compete for polyglutamylation and/or binding to intracellular enzyme targets. Human tumor cells including wild-type (WT) and R5 (RFC-null) HeLa cells express high levels of PCFT protein. C1 and C2 inhibited proliferation of R5 cells 3 to 4 times more potently than WT cells or R5 cells transfected with RFC. Transport of C1 and C2 was virtually identical between WT and R5 cells, establishing that differences in drug sensitivities between sublines were independent of PCFT transport. Steady-state intracellular [3H]THF cofactors derived from [3H]5-formyl-THF were depleted in R5 cells compared with those in WT cells, an effect exacerbated by C1 and C2. Whereas C1 and C2 polyglutamates accumulated to similar levels in WT and R5 cells, there were differences in polyglutamyl distributions in favor of the longest chain length forms. In severe combined immunodeficient mice, the antitumor efficacies of C1 and C2 were greater toward subcutaneous R5 tumors than toward WT tumors, confirming the collateral drug sensitivities observed in vitro. Thus, solid tumor-targeted antifolates with PCFT-selective cellular uptake should have enhanced activities toward tumors lacking RFC function, reflecting contraction of THF cofactor pools.

Footnotes

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

  • This study was supported by the National Institutes of Health National Cancer Institute [Grants CA53535, CA152316, CA125153]; the Barbara Ann Karmanos Cancer Institute; and the Mesothelioma Applied Research Foundation. S.K.D. was supported by a Doctoral Research Award from the Canadian Institute of Health Research.

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

    http://dx.doi.org/10.1124/mol.112.079004.

  • ABBREVIATIONS:

    MTX
    methotrexate
    PMX
    pemetrexed
    RFC
    reduced folate carrier
    PCFT
    proton-coupled folate transporter
    FR
    folate receptor
    THF
    tetrahydrofolate
    5-CHO-THF
    5-formyl-tetrahydrofolate
    C1
    compound 1
    C2
    compound 2
    hRFC
    human reduced folate carrier
    hPCFT
    human proton-coupled folate transporter
    HA
    hemagglutinin
    WT
    wild-type
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    MES
    4-morphilinopropane sulfonic acid
    DPBS
    Dulbecco's phosphate-buffered saline
    PIPES
    piperazine-N,N′-bis(2-ethanesulfonic acid)
    HPLC
    high-performance liquid chromatography
    SCID
    severe combined immunodeficient
    LMX
    lometrexol
    RTX
    raltitrexed
    PT523
    Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine
    PG
    polyglutamate
    FPGS
    folylpolyglutamate synthetase
    ABC
    ATP-binding cassette.

  • Received March 29, 2012.
  • Accepted June 26, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (4)
Molecular Pharmacology
Vol. 82, Issue 4
1 Oct 2012
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Research ArticleArticle

Impact of RFC on PCFT-Targeted Therapeutics

Sita Kugel Desmoulin, Lei Wang, Lisa Polin, Kathryn White, Juiwanna Kushner, Mark Stout, Zhanjun Hou, Christina Cherian, Aleem Gangjee and Larry H. Matherly
Molecular Pharmacology October 1, 2012, 82 (4) 591-600; DOI: https://doi.org/10.1124/mol.112.079004

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Research ArticleArticle

Impact of RFC on PCFT-Targeted Therapeutics

Sita Kugel Desmoulin, Lei Wang, Lisa Polin, Kathryn White, Juiwanna Kushner, Mark Stout, Zhanjun Hou, Christina Cherian, Aleem Gangjee and Larry H. Matherly
Molecular Pharmacology October 1, 2012, 82 (4) 591-600; DOI: https://doi.org/10.1124/mol.112.079004
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