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Article

Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma

1
Department of Research & Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA 91343, USA
2
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
3
Jonnson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA 90095, USA
4
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
5
Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(1), 344; https://doi.org/10.3390/ijms21010344
Received: 12 December 2019 / Revised: 27 December 2019 / Accepted: 31 December 2019 / Published: 5 January 2020
(This article belongs to the Special Issue Protein Synthesis and Disease)
Internal ribosome entry site (IRES)-mediated protein synthesis has been demonstrated to play an important role in resistance to mechanistic target of rapamycin (mTOR) targeted therapies. Previously, we have demonstrated that the IRES trans-acting factor (ITAF), hnRNP A1 is required to promote IRES activity and small molecule inhibitors which bind specifically to this ITAF and curtail IRES activity, leading to mTOR inhibitor sensitivity. Here we report the identification of riluzole (Rilutek®), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), via an in silico docking analysis of FDA-approved compounds, as an inhibitor of hnRNP A1. In a riluzole-bead coupled binding assay and in surface plasmon resonance imaging analyses, riluzole was found to directly bind to hnRNP A1 and inhibited IRES activity via effects on ITAF/RNA-binding. Riluzole also demonstrated synergistic anti-glioblastoma (GBM) affects with mTOR inhibitors in vitro and in GBM xenografts in mice. These data suggest that repurposing riluzole, used in conjunction with mTOR inhibitors, may serve as an effective therapeutic option in glioblastoma. View Full-Text
Keywords: riluzole; hnRNP A1; ITAF; mTOR; drug resistance; glioblastoma riluzole; hnRNP A1; ITAF; mTOR; drug resistance; glioblastoma
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MDPI and ACS Style

Benavides-Serrato, A.; Saunders, J.T.; Holmes, B.; Nishimura, R.N.; Lichtenstein, A.; Gera, J. Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma. Int. J. Mol. Sci. 2020, 21, 344. https://doi.org/10.3390/ijms21010344

AMA Style

Benavides-Serrato A, Saunders JT, Holmes B, Nishimura RN, Lichtenstein A, Gera J. Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma. International Journal of Molecular Sciences. 2020; 21(1):344. https://doi.org/10.3390/ijms21010344

Chicago/Turabian Style

Benavides-Serrato, Angelica, Jacquelyn T. Saunders, Brent Holmes, Robert N. Nishimura, Alan Lichtenstein, and Joseph Gera. 2020. "Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma" International Journal of Molecular Sciences 21, no. 1: 344. https://doi.org/10.3390/ijms21010344

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