Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma

Jennifer M. Munson, Levi Fried, Sydney A. Rowson, Michael Y. Bonner, Lohitash Karumbaiah, Begoña Diaz, Sara A. Courtneidge, Ulla G. Knaus, Daniel J. Brat, Jack L. Arbiser, Ravi V. Bellamkonda

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the efficacy of chemotherapy. We report a new anti-invasive small molecule, Imipramine Blue (IB), which inhibits invasion of glioma in vitro when tested against several models. IB inhibits NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-mediated reactive oxygen species generation and alters expression of actin regulatory elements. In vivo, liposomal IB (nano-IB) halts invasion of glioma, leading to a more compact tumor in an aggressively invasive RT2 syngeneic astrocytoma rodent model. When nano-IB therapy was followed by liposomal doxorubicin (nano-DXR) chemotherapy, the combination therapy prolonged survival compared to nano-IB or nano-DXR alone. Our data demonstrate that nano-IB-mediated containment of diffuse glioma enhanced the efficacy of nano-DXR chemotherapy, demonstrating the promise of an anti-invasive compound as an adjuvant treatment for glioma.

Original languageEnglish (US)
Article number127ra36
JournalScience translational medicine
Volume4
Issue number127
DOIs
StatePublished - Mar 28 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Munson, J. M., Fried, L., Rowson, S. A., Bonner, M. Y., Karumbaiah, L., Diaz, B., Courtneidge, S. A., Knaus, U. G., Brat, D. J., Arbiser, J. L., & Bellamkonda, R. V. (2012). Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma. Science translational medicine, 4(127), [127ra36]. https://doi.org/10.1126/scitranslmed.3003016