SapC-DOPS-induced lysosomal cell death synergizes with TMZ in glioblastoma
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Jeffrey Wojton1, Walter Hans Meisen1, Naduparambil K. Jacob2, Amy Haseley Thorne4, Jayson Hardcastle5, Nicholas Denton1, Zhengtao Chu6, Nina Dmitrieva1, Rachel Marsh1, Erwin G. Van Meir7, Chang-Hyuk Kwon1,3, Arnab Chakravarti2, Xiaoyang Qi6,* and Balveen Kaur1,*
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 Solid-Tumor Program at the James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH
4 Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California
5 Departments of Medical Oncology and Molecular Medicine, Mayo Clinic, Rochester, MN
6 The Vontz Center for Molecular Studies, Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
7 Departments of Neurosurgery and Hematology and Medical Oncology, Winship Cancer, Winship Cancer Institute and School of Medicine, Emory University School of Medicine, Atlanta, GA
* These authors contributed equally to this work
Balveen Kaur, email:
Xiaoyang Qi, email:
Keywords: SapC-DOPS, glioblastoma, lysosomal dysfunction, TMZ, synergy
Received: July 7, 2014 Accepted: July 16, 2014 Published: July 17, 2014
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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