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

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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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Abbreviations

GBM:

Glioblastoma

PPF:

Propentofylline

TMZ:

Temozolomide

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Acknowledgments

This work was supported by Ben & Catherine IVY Foundation, NIH grants NS86853 and P50 CA108961.

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Correspondence to Nhan L. Tran.

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Harshil D. Dhruv and Alison Roos have contributed equally to this work.

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Dhruv, H.D., Roos, A., Tomboc, P.J. et al. Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway. J Neurooncol 126, 397–404 (2016). https://doi.org/10.1007/s11060-015-1981-0

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  • DOI: https://doi.org/10.1007/s11060-015-1981-0

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