Oncotarget

Research Papers:

Acid ceramidase is a novel drug target for pediatric brain tumors

Ninh B. Doan, Ha S. Nguyen, Andrew Montoure, Mona M. Al-Gizawiy, Wade M. Mueller, Shekar Kurpad, Scott D. Rand, Jennifer M. Connelly, Christopher R. Chitambar, Kathleen M. Schmainda and Shama P. Mirza _

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Oncotarget. 2017; 8:24753-24761. https://doi.org/10.18632/oncotarget.15800

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Abstract

Ninh B. Doan1,2, Ha S. Nguyen2, Andrew Montoure2, Mona M. Al-Gizawiy3, Wade M. Mueller2, Shekar Kurpad2, Scott D. Rand3, Jennifer M. Connelly4, Christopher R. Chitambar4, Kathleen M. Schmainda3,6, Shama P. Mirza1,7,8

1Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

2Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

3Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

4Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

5Department of Medicine, Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

6Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

7Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

8Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, Wisconsin, 53211, USA

Correspondence to:

Ninh B. Doan, email: [email protected]

Keywords: pediatric glioblastoma, acid ceramidase inhibitors, carmofur, glioblastoma, medulloblastoma

Received: September 12, 2016     Accepted: February 15, 2017     Published: March 01, 2017

ABSTRACT

Pediatric brain tumors are the most common solid tumors in children and are also a leading culprit of cancer-related fatalities in children. Pediatric brain tumors remain hard to treat. In this study, we demonstrated that medulloblastoma, pediatric glioblastoma, and atypical teratoid rhabdoid tumors express significant levels of acid ceramidase, where levels are highest in the radioresistant tumors, suggesting that acid ceramidase may confer radioresistance. More importantly, we also showed that acid ceramidase inhibitors are highly effective at targeting these pediatric brain tumors with low IC50 values (4.6–50 μM). This data suggests acid ceramidase as a novel drug target for adjuvant pediatric brain tumor therapies. Of these acid ceramidase inhibitors, carmofur has seen clinical use in Japan since 1981 for colorectal cancers and is a promising drug to undergo further animal studies and subsequently a clinical trial as a treatment for pediatric patients with brain tumors.


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