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Aurintricarboxylic Acid Proposed as Basis of New Glioblastoma Treatment Plan

By BiotechDaily International staff writers
Posted on 01 Feb 2017
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Image: A ball-and-stick model of the aurintricarboxylic acid (ATA) molecule (Photo courtesy of Wikimedia Commons).
Image: A ball-and-stick model of the aurintricarboxylic acid (ATA) molecule (Photo courtesy of Wikimedia Commons).
The compound aurintricarboxylic acid (ATA) has been identified as a possible new therapeutic agent for treatment of patients with the deadly brain cancer glioblastoma multiforme (GBM).

GBM is the most common primary tumor of the central nervous system and is almost always fatal. The aggressive invasion of GBM cells into the surrounding normal brain makes complete surgical removal impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to eight months for patients with recurrent GBM. Treatment of glioblastoma usually comprises surgical removal of the tumor followed by radiation treatment and chemotherapy using the drug temozolomide (TMZ). However, the penetration of the tumor into adjacent brain tissue prevents the surgical removal of all tumor cells, which usually develop resistance to TMZ.

Investigators at the Translational Genomics Research Institute have been seeking a better approach for treating GBM. In previous studies they had found that development of GBM was linked to TWEAK (Tumor necrosis factor-like weak inducer of apoptosis), a member of the tumor necrosis factor (TNF) superfamily, which could stimulate glioma cell invasion and survival via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-kappaB.

In the current study, to discover small molecule inhibitors capable of disrupting the TWEAK-Fn14 signaling axis, the investigators utilized a cell-based drug-screening assay using HEK293 cells engineered to express both Fn14 and a NF-kappaB-driven firefly luciferase reporter protein.

The investigators reported in the January 17, 2017, online edition of the journal Oncotarget that during screening of 1280 pharmacologically active compounds they had identified aurintricarboxylic acid (ATA) as an agent that suppressed TWEAK-Fn14-NF-kappaB dependent signaling, but not TNFalpha-TNFR-NF-kappaB driven signaling. ATA is used to inhibit protein biosynthesis in its initial stages, and it is frequently used in biological experiments as a protein inhibitor.

The investigators showed that ATA repressed TWEAK-induced glioma cell chemotactic migration and invasion via inhibition of Rac1 activation but had no effect on cell viability or Fn14 expression. In addition, ATA treatment enhanced glioma cell sensitivity to both TMZ and radiation-induced cell death.

"These data demonstrate that ATA presents a scaffold structure that could be modified in ways to improve its properties and to develop as a potential therapeutic agent to limit invasion and enhance chemotherapeutic drug efficacy in GBM," said senior author Dr. Nhan Tran, associate professor of cancer and cell biology at the Translational Genomics Research Institute.

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