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

• Type of Material: Article
• Authors: Jeffrey Wojton, Ohio State University; Walter Hans Meisen, Ohio State University; Naduparambil K. Jacob, Ohio State University; Amy Haseley Thorne, University of California San Diego; Jayson Hardcastle, Mayo Clinic; Nicholas Denton, Ohio State University; Zhengtao Chu, University of Cincinnati; Nina Dmitrieva, Ohio State University; Rachel Marsh, Ohio State University; Erwin Van Meir, Emory University; Chang-Hyuk Kwon, Ohio State University; Arnab Chakravarti, Ohio State University; Xiaoyang Qi, University of Cincinnati; Balveen Kaur, Ohio State University
• Language: English
• Date: 2014-07-17
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Wojton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.2232
• Title of Journal or Parent Work: Oncotarget
• Volume: 5
• Issue: 20
• Start Page: 9703
• End Page: 9709
• Keywords: RESISTANCE; CONCOMITANT; GLIOMAS; Oncology; lysosomal dysfunction; Life Sciences & Biomedicine; Science & Technology; SapC-DOPS; SPHINGOLIPIDS; synergy; TMZ; glioblastoma; RADIOTHERAPY; SURVIVAL; ADJUVANT TEMOZOLOMIDE; Cell Biology; APOPTOSIS
• Research Categories: Biology, Neuroscience; Health Sciences, Oncology

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.