Oncotarget

Research Papers:

Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency

Ninh B. Doan, Hisham Alhajala, Mona M. Al-Gizawiy, Wade M. Mueller, Scott D. Rand, Jennifer M. Connelly, Elizabeth J. Cochran, Christopher R. Chitambar, Paul Clark, John Kuo, Kathleen M. Schmainda and Shama P. Mirza _

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Oncotarget. 2017; 8:112662-112674. https://doi.org/10.18632/oncotarget.22637

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Abstract

Ninh B. Doan1,2, Hisham Alhajala3, Mona M. Al-Gizawiy4, Wade M. Mueller2, Scott D. Rand4, Jennifer M. Connelly5, Elizabeth J. Cochran 6, Christopher R. Chitambar3, Paul Clark7, John Kuo7, Kathleen M. Schmainda3,8 and Shama P. Mirza1,9,10

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

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

3Medicine, Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

4Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

5Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

6Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

7Department of Neurological Surgery and Human Oncology, University of Wisconsin, Madison, Wisconsin, 53792, USA

8Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

9Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA

10Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, Wisconsin, 53211, USA

Correspondence to:

Shama P. Mirza, email: mirza@uwm.edu

Keywords: glioblastoma, acid ceramidase, carmofur, glioblastoma cancer stem cells (GSCs), overall survival

Received: December 28, 2016     Accepted: September 30, 2017     Published: November 07, 2017

ABSTRACT

Glioblastoma remains the most common, malignant primary cancer of the central nervous system with a low life expectancy and an overall survival of less than 1.5 years. The treatment options are limited and there is no cure. Moreover, almost all patients develop recurrent tumors, which typically are more aggressive. Therapeutically resistant glioblastoma or glioblastoma stem-like cells (GSCs) are hypothesized to cause this inevitable recurrence. Identifying prognostic biomarkers of glioblastoma will potentially advance knowledge about glioblastoma tumorigenesis and enable discovery of more effective therapies. Proteomic analysis of more than 600 glioblastoma-specific proteins revealed, for the first time, that expression of acid ceramidase (ASAH1) is associated with poor glioblastoma survival. CD133+ GSCs express significantly higher ASAH1 compared to CD133- GSCs and serum-cultured glioblastoma cell lines, such as U87MG. These findings implicate ASAH1 as a plausible independent prognostic marker, providing a target for a therapy tailored toward GSCs. We further demonstrate that ASAH1 inhibition increases cellular ceramide level and induces apoptosis. Strikingly, U87MG cells, and three different patient-derived glioblastoma stem-like cancer cell lines were efficiently killed, through apoptosis, by three different known ASAH1 inhibitors with IC50’s ranging from 11–104 μM. In comparison, the standard glioblastoma chemotherapy agent, temozolomide, had minimal GSC-targeted effects at comparable or even higher concentrations (IC50 > 750 μM against GSCs). ASAH1 is identified as a de novo glioblastoma drug target, and ASAH1 inhibitors, such as carmofur, are shown to be highly effective and to specifically target glioblastoma GSCs. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, a major bottleneck in glioblastoma treatment. It has been approved in Japan since 1981 for colorectal cancer therapy. Therefore, it is poised for repurposing and translation to glioblastoma clinical trials.


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