Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33

Saritha Tantravedi, Farhad Vesuna, Paul T. Winnard, Allison Martin, Michael Lim, Charles G. Eberhart, Cynthia Berlinicke, Eric Raabe, Paul J. van Diest, Venu Raman

Research output: Contribution to journalArticle

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Abstract

Medulloblastoma is the most common malignant tumor that arises from the cerebellum of the central nervous system. Clinically, medulloblastomas are treated by surgery, radiation, and chemotherapy, all of which result in toxicity and morbidity. Recent reports have identified that DDX3, a member of the RNA helicase family, is mutated in medulloblastoma. In this study, we demonstrate the role of DDX3 in driving medulloblastoma. With the use of a small molecule inhibitor of DDX3, RK-33, we could inhibit growth and promote cell death in two medulloblastoma cell lines, DAOY and UW228, with IC50 values of 2.5 μM and 3.5 μM, respectively. Treatment of DAOY and UW228 cells with RK-33 caused a G1 arrest, resulted in reduced TCF reporter activity, and reduced mRNA expression levels of downstream target genes of the WNT pathway, such as Axin2, CCND1, MYC, and Survivin. In addition, treatment of DAOY and UW228 cells with a combination of RK-33 and radiation exhibited a synergistic effect. Importantly, the combination of RK-33 and 5 Gy radiation caused tumor regression in a mouse xenograft model of medulloblastoma. Using immunohistochemistry, we observed DDX3 expression in both pediatric (55%) and adult (66%) medulloblastoma patients. Based on these results, we conclude that RK-33 is a promising radiosensitizing agent that inhibits DDX3 activity and down-regulates WNT/β-catenin signaling and could be used as a frontline therapeutic strategy for DDX3-expressing medulloblastomas in combination with radiation.

Original languageEnglish (US)
Pages (from-to)96-105
Number of pages10
JournalTranslational Oncology
Volume12
Issue number1
DOIs
StatePublished - Jan 2019
Externally publishedYes

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Medulloblastoma
Radiation
Radiation-Sensitizing Agents
RNA Helicases
Radiation Dosage
Catenins
Heterografts
Cerebellum
Inhibitory Concentration 50
Neoplasms
Cell Death
Therapeutics
Down-Regulation
Central Nervous System
Immunohistochemistry
Pediatrics
Morbidity
Drug Therapy
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tantravedi, S., Vesuna, F., Winnard, P. T., Martin, A., Lim, M., Eberhart, C. G., ... Raman, V. (2019). Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33. Translational Oncology, 12(1), 96-105. https://doi.org/10.1016/j.tranon.2018.09.002

Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33. / Tantravedi, Saritha; Vesuna, Farhad; Winnard, Paul T.; Martin, Allison; Lim, Michael; Eberhart, Charles G.; Berlinicke, Cynthia; Raabe, Eric; van Diest, Paul J.; Raman, Venu.

In: Translational Oncology, Vol. 12, No. 1, 01.2019, p. 96-105.

Research output: Contribution to journalArticle

Tantravedi, S, Vesuna, F, Winnard, PT, Martin, A, Lim, M, Eberhart, CG, Berlinicke, C, Raabe, E, van Diest, PJ & Raman, V 2019, 'Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33', Translational Oncology, vol. 12, no. 1, pp. 96-105. https://doi.org/10.1016/j.tranon.2018.09.002
Tantravedi, Saritha ; Vesuna, Farhad ; Winnard, Paul T. ; Martin, Allison ; Lim, Michael ; Eberhart, Charles G. ; Berlinicke, Cynthia ; Raabe, Eric ; van Diest, Paul J. ; Raman, Venu. / Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33. In: Translational Oncology. 2019 ; Vol. 12, No. 1. pp. 96-105.
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