title: SapC-DOPS-induced lysosomal cell death synergizes with TMZ in glioblastoma.
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.
authors.affiliation: Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wojton
authors.affiliation: Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Walter Hans
authors.initials: WH
authors.lastname: Meisen
authors.affiliation: Department of Radiation-Oncology, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Naduparambil K
authors.initials: NK
authors.lastname: Jacob
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California.
authors.forename: Amy Haseley
authors.initials: AH
authors.lastname: Thorne
authors.affiliation: Departments of Medical Oncology and Molecular Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Jayson
authors.initials: J
authors.lastname: Hardcastle
authors.affiliation: Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Denton
authors.affiliation: The Vontz Center for Molecular Studies, Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Chu
authors.affiliation: Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Nina
authors.initials: N
authors.lastname: Dmitrieva
authors.affiliation: Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Rachel
authors.initials: R
authors.lastname: Marsh
authors.affiliation: Departments of Neurosurgery and Hematology and Medical Oncology, Winship Cancer, Winship Cancer Institute and School of Medicine, Emory University School of Medicine, Atlanta, GA.
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.affiliation: 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.
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Kwon
authors.affiliation: Department of Radiation-Oncology, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: The Vontz Center for Molecular Studies, Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D049329:Nanostructures / Q000008:administration & dosage*; D010718:Phosphatidylserines / Q000494:pharmacology*; D011897:Random Allocation; D049231:Saposins / Q000008:administration & dosage / Q000494:pharmacology*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D010718:Phosphatidylserines; D049231:Saposins; C042511:1,2-dioleoylphosphatidylserine; D003606:Dacarbazine; D000077204:Temozolomide