Oncotarget

Research Papers:

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

Jeffrey Wojton, Walter Hans Meisen, Naduparambil K. Jacob, Amy Haseley Thorne, Jayson Hardcastle, Nicholas Denton, Zhengtao Chu, Nina Dmitrieva, Rachel Marsh, Erwin G. Van Meir, Chang-Hyuk Kwon, Arnab Chakravarti, Xiaoyang Qi and Balveen Kaur _

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Oncotarget. 2014; 5:9703-9709. https://doi.org/10.18632/oncotarget.2232

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Abstract

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

Correspondence:

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

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.


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