Anti-Invasive Adjuvant Therapy with Imipramine Blue Enhances Chemotherapeutic Efficacy Against Glioma

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.

The NADPH Oxidase Inhibitor Imipramine-Blue in the Treatment of Burkitt Lymphoma

“…The dissemination of BL2B95 cells via the lymphatics was unaltered, as was the ragged appearance of the tumor borders. This seems to be in contrast to the findings of the anti-invasive effects of imipramine-blue in a rodent astrocytoma (RT2) model (1). However, these differences may reside in inherent differences of the chick CAM model and the rat model, different modes of migration of the analyzed tumor cells, or in the different application forms of the drug.…”

“…Among these, MFHAS1 may be of special interest. MFHAS1 is a potential oncogene that may cause B-cell lymphoma and is downregulated at the transcriptional level by imipramine-blue treatment (1,34). The inhibition of MFHAS1 may explain the high sensitivity of the Burkitt lymphoma cell lines toward imipramine-blue treatment.…”

“…Whether the observed effects rely mainly on NOX4 inhibition or if offtarget effects are involved is still unclear. It was shown by Munson and colleagues (1) that imipramine-blue application in vivo influences a number of genes in RT2 tumors (1). Among these, MFHAS1 may be of special interest.…”

“…Treatment with imipramine-blue induced the formation of tumors with a more compact morphology. It reduced invasion of tumor cells into healthy tissues and prolonged survival after combination therapy with liposomal doxorubicin (1). The target protein of imipramine-blue, NADPH oxidase 4 (NOX4), is involved in antiapoptotic signaling, including the NF-kB signaling pathway, which is highly active in many nonHodgkin lymphomas (15,(17)(18)(19).…”

Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth

“…Another interesting issue related to anti-VEGF therapy is that inhibition of tumor angiogenesis can elevate hypoxia in tumor tissues, leading to increased levels of NADPH oxidase. In hemangiomas, for example, expression levels of PlGF, angiopoietin-2, and notch ligand Dll4 are subsequently regulated by NADPH, resulting in altered tumor angiogenesis (38,39). Again, hypoxia-induced VEGF expression coordinately interacts with PlGF, angiopoietin-1, and Dll4 to coordinately modulate angiogenesis, vessel remodeling, and vascular functions.…”