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Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway. | LitMetric

AI Article Synopsis

  • Glioblastoma (GBM) is the most common and aggressive brain tumor, leading to poor survival rates, with only 14.6 months for newly diagnosed cases and 8 months for recurrent instances.
  • TROY, a protein involved in GBM cell invasion and therapy resistance, was identified as a key target; reducing its expression can improve response to the standard treatment temozolomide and prolong survival in experimental models.
  • Propentofylline (PPF), a drug with known safety in other conditions, has shown promise in lowering TROY levels, inhibiting GBM cell invasion, and enhancing sensitivity to temozolomide, suggesting a potential new therapeutic strategy for treating GBM.

Article Abstract

Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection 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 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. Knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer's disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. Here we showed that PPF decreased GBM cell expression of TROY, inhibited glioma cell invasion, and sensitized GBM cells to TMZ. Mechanistically, PPF decreased glioma cell invasion by modulating TROY expression and downstream signaling, including AKT, NF-κB, and Rac1 activation. Thus, PPF may provide a pharmacologic approach to target TROY, inhibit cell invasion, and reduce therapeutic resistance in GBM.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733619PMC
http://dx.doi.org/10.1007/s11060-015-1981-0DOI Listing

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