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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Activation of Alternate Prosurvival Pathways Accounts for Acquired Sunitinib Resistance in U87MG Glioma Xenografts

Qingyu Zhou, Hua Lv, Amin R. Mazloom, Huilei Xu, Avi Ma'ayan and James M. Gallo
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 509-519; DOI: https://doi.org/10.1124/jpet.112.196097
Qingyu Zhou
Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York, Mount Sinai School of Medicine, New York, New York
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Hua Lv
Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York, Mount Sinai School of Medicine, New York, New York
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Amin R. Mazloom
Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York, Mount Sinai School of Medicine, New York, New York
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Huilei Xu
Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York, Mount Sinai School of Medicine, New York, New York
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Avi Ma'ayan
Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York, Mount Sinai School of Medicine, New York, New York
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James M. Gallo
Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York, Mount Sinai School of Medicine, New York, New York
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Abstract

Acquired drug resistance represents a major obstacle to using sunitinib for the treatment of solid tumors. Here, we examined the cellular and molecular alterations in tumors that are associated with acquired brain tumor resistance to sunitinib by using an in vivo model. U87MG tumors obtained from nude mice that received sunitinib (40 mg/kg/day) for 30 days were classified into sunitinib-sensitive and -resistant groups based on tumor volume and underwent targeted gene microarray and protein array analyses. The expression of several angiogenesis-associated genes was significantly modulated in sunitinib-treated tumors compared with those in control tumors (p < 0.05), whereas no significant differences were observed between sunitinib-sensitive and -resistant tumors (p > 0.05). Tumor vasculature based on microvessel density, neurogenin 2 chondroitin sulfate proteoglycan density, and α-smooth muscle actin density was also similar in sunitinib-treatment groups (p > 0.05). The moderate increase in unbound sunitinib tumor-to-plasma area-under-the-curve ratio in sunitinib-resistant mice was accompanied by up-regulated ATP-binding cassette G2 expression in tumor. The most profound difference between the sunitinib-sensitive and -resistant groups was found in the expression of several phosphorylated proteins involved in intracellular signaling. In particular, phospholipase C-γ1 phosphorylation in sunitinib-resistant tumors was up-regulated by 2.6-fold compared with that in sunitinib-sensitive tumors (p < 0.05). In conclusion, acquired sunitinib resistance in U87MG tumors is not associated with revascularization in tumors, but rather with the activation of alternate prosurvival pathways involved in an escape mechanism facilitating tumor growth and possibly insufficient drug uptake in tumor cells caused by an up-regulated membrane efflux transporter.

Footnotes

  • This study was supported by the National Institutes of Health National Cancer Institute [Grant CA072937]; and the National Institutes of Health National Institute of General Medical Sciences [Grant P50GM071558-03].

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

    http://dx.doi.org/10.1124/jpet.112.196097.

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

  • ABBREVIATIONS:

    VEGF
    vascular endothelial growth factor
    ABCB1
    ATP-binding cassette B1
    ABCG2
    ATP-binding cassette G2
    ANOVA
    analysis of variance
    AUC
    area under the curve
    c-Jun
    Jun proto-oncogene
    CREB
    cAMP response element-binding protein
    CT
    cycle threshold
    CT
    control tumor
    ERK1/2
    extracellular signal-regulated kinase 1/2
    p-ERK1/2
    phosphorylated ERK1/2
    GSK3α/β
    glycogen synthase kinase 3α/β
    p-GSK3α/β
    phosphorylated GSK3α/β
    HSP27
    heat shock protein 27
    IF
    interstitial fluid
    IL-8
    interleukin-8
    JNK
    c-Jun NH2-terminal kinase
    p-c-Jun
    phosphorylated c-Jun
    MMP
    matrix metallopeptidase
    NG2
    neurogenin 2 chondroitin sulfate proteoglycan
    NIH
    National Institutes of Health
    PCA
    principal component analysis
    PCR
    polymerase chain reaction
    PK
    pharmacokinetic
    PLC-γ1
    phospholipase C-γ1
    p-PLC-γ1
    phosphorylated PLC-γ1
    RSK1/2/3
    ribosomal S6 kinase 1/2/3
    RT
    resistant tumor
    α-SMA
    α-smooth muscle actin
    ST
    sensitive tumor
    STAT5α/β
    signal transducers and activators of transcription 5α/β
    U73122
    1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione.

  • Received May 2, 2012.
  • Accepted August 3, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Activated Prosurvival Pathways in Sunitinib-Resistant Tumor

Qingyu Zhou, Hua Lv, Amin R. Mazloom, Huilei Xu, Avi Ma'ayan and James M. Gallo
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 509-519; DOI: https://doi.org/10.1124/jpet.112.196097

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Activated Prosurvival Pathways in Sunitinib-Resistant Tumor

Qingyu Zhou, Hua Lv, Amin R. Mazloom, Huilei Xu, Avi Ma'ayan and James M. Gallo
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 509-519; DOI: https://doi.org/10.1124/jpet.112.196097
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