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Oncotarget. 2014 Oct 30;5(20):9703-9.

SapC-DOPS-induced lysosomal cell death synergizes with TMZ in glioblastoma.

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Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH.
Department of Radiation-Oncology, The Ohio State University Medical Center, Columbus, OH.
Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California.
Departments of Medical Oncology and Molecular Medicine, Mayo Clinic, Rochester, MN.
The Vontz Center for Molecular Studies, Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
Departments of Neurosurgery and Hematology and Medical Oncology, Winship Cancer, Winship Cancer Institute and School of Medicine, Emory University School of Medicine, Atlanta, GA.
Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH. Solid-Tumor Program at the James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH.


SapC-DOPS is a novel nanotherapeutic that has been shown to target and induce cell death in a variety of cancers, including glioblastoma (GBM). GBM is a primary brain tumor known to frequently demonstrate resistance to apoptosis-inducing therapeutics. Here we explore the mode of action for SapC-DOPS in GBM, a treatment being developed by Bexion Pharmaceuticals for clinical testing in patients. SapC-DOPS treatment was observed to induce lysosomal dysfunction of GBM cells characterized by decreased glycosylation of LAMP1 and altered proteolytic processing of cathepsin D independent of apoptosis and autophagic cell death. We observed that SapC-DOPS induced lysosomal membrane permeability (LMP) as shown by LysoTracker Red and Acridine Orange staining along with an increase of sphingosine, a known inducer of LMP. Additionally, SapC-DOPS displayed strong synergistic interactions with the apoptosis-inducing agent TMZ. Collectively our data suggest that SapC-DOPS induces lysosomal cell death in GBM cells, providing a new approach for treating tumors resistant to traditional apoptosis-inducing agents.

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