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

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

Author information

1
Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH.
2
Department of Radiation-Oncology, The Ohio State University Medical Center, Columbus, OH.
3
Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California.
4
Departments of Medical Oncology and Molecular Medicine, Mayo Clinic, Rochester, MN.
5
The Vontz Center for Molecular Studies, Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
6
Departments of Neurosurgery and Hematology and Medical Oncology, Winship Cancer, Winship Cancer Institute and School of Medicine, Emory University School of Medicine, Atlanta, GA.
7
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.

Abstract

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.

PMID:
25210852
PMCID:
PMC4259431
DOI:
10.18632/oncotarget.2232
[Indexed for MEDLINE]
Free PMC Article

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