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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Activation of Alternate Pro-Survival 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 August 6, 2012, jpet.112.196097; DOI: https://doi.org/10.1124/jpet.112.196097
Qingyu Zhou
1 University of South Florida College of Pharmacy;
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Hua Lv
2 Mount Sinai School of Medicine
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Amin R Mazloom
2 Mount Sinai School of Medicine
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Huilei Xu
2 Mount Sinai School of Medicine
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Avi Ma'ayan
2 Mount Sinai School of Medicine
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James M Gallo
2 Mount Sinai School of Medicine
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Abstract

Acquired drug resistance represents a major obstacle to using sunitinib for the treatment of solid tumors. Here, we examined cellular and molecular alterations in tumors that are associated with acquired brain tumor resistance to sunitinib using an in vivo model. U87MG tumors obtained from nude mice that received sunitinib 40 mg/kg/day for 30 days were classified as 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 (NG2) density and α-smooth muscle actin (α-SMA) density was also similar in sunitinib-treatment groups (p > 0.05). The moderate increase in unbound sunitinib tumor-to-plasma area-under-the-curve (AUC) ratio in sunitinib-resistant mice was accompanied by upregulated ABCG2 expression in tumor. The most profound difference between sunitinib-sensitive and -resistant groups was found in the expression of several phosphorylated proteins involved in intracellular signaling. In particular, phospholipase C-γ1 (PLC-γ1) phosphorylation in sunitinib-resistant tumors was upregulated by 2.6 folds 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 activation of alternate pro-survival pathways involved in an escape mechanism facilitating tumor growth and possibly insufficient drug uptake in tumor cells due to an upregulated membrane efflux transporter.

  • angiogenesis
  • anticancer agents
  • kinases
  • pharmacokinetics
  • resistance
  • Received May 2, 2012.
  • Revision received August 2, 2012.
  • Accepted August 3, 2012.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Activation of Alternate Pro-Survival 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 August 6, 2012, jpet.112.196097; DOI: https://doi.org/10.1124/jpet.112.196097

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Activation of Alternate Pro-Survival 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 August 6, 2012, jpet.112.196097; DOI: https://doi.org/10.1124/jpet.112.196097
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