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

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

doi:10.18632/oncotarget.2232

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.

Highlights

Gliomas constitute nearly 70% of all malignant primary brain tumors[1] and have been wellcharacterized for their inherent and acquired resistance to chemotherapy and radiotherapy.[2, 3] Despite surgical resection, chemotherapy with temozolomide (TMZ), and radiotherapy median survival of patients diagnosed with a glioblastoma (GBM) is less than 15 months.[4, 5] Part of the recalcitrant nature of these tumors is due to their intrinsic resistance to therapy-induced apoptosis and enhanced survival signaling.[6]
We demonstrated the ability of systemically administered saposin www.impactjournals.com/oncotargetC (SapC)-DOPS nanovesicles to target brain tumors and the tumor-associated vasculature resulting in significant antitumor effects.[8]
Treatment of neuroblastoma and pancreatic cancer cells with SapCDOPS has been shown to generate increased ceramide levels through activation of acid sphingomyelinase, leading to subsequent caspase activation and apoptosis. [7, 9] most GBM cells are intrinsically resistant to apoptosis and the mechanism of cell death induced by SapC-DOPS in GBM remains to be elucidated

Summary

Introduction

Gliomas constitute nearly 70% of all malignant primary brain tumors[1] and have been wellcharacterized for their inherent and acquired resistance to chemotherapy and radiotherapy.[2, 3] Despite surgical resection, chemotherapy with temozolomide (TMZ), and radiotherapy median survival of patients diagnosed with a glioblastoma (GBM) is less than 15 months.[4, 5] Part of the recalcitrant nature of these tumors is due to their intrinsic resistance to therapy-induced apoptosis and enhanced survival signaling.[6]. In this study we examined the activation of key downstream molecular signaling events following SapC-DOPS treatment in GBM and report a novel mechanism of action for SapC-DOPS-induced cell death, which can be combined with TMZ to improve efficacy.

Results

Conclusion