title: Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic antitumor effects.
abstract: BACKGROUND
  Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic herpes simplex virus-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for antitumor efficacy.
  
  
  METHODS
  The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western blot assays were used to evaluate induction of estrogen receptor (ER) stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Antitumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan-Meier curves and two-sided log-rank test.
  
  
  RESULTS
  Combination treatment with bortezomib and oHSV (34.5ENVE), displayed strong synergistic interaction in ovarian cancer, head and neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK, and IRE1α (Western blot analysis) and the UPR (induction of hsp40, 70, and 90). Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (P < 0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced antitumor efficacy in multiple different tumor models in vivo.
  
  
  CONCLUSIONS
  The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib-induced UPR and warrants future clinical testing in patients.
authors.affiliation: Authors' Affiliations: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences;
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Authors' Affiliations: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences; Biomedical Science Major;
authors.forename: Brian S
authors.initials: BS
authors.lastname: Hurwitz
authors.affiliation: Integrated Biomedical Sciences Graduate Program;
authors.forename: Chelsea
authors.initials: C
authors.lastname: Bolyard
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery;
authors.forename: Jun-Ge
authors.initials: JG
authors.lastname: Yu
authors.affiliation: Center for Biostatistics;
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology;
authors.forename: Karuppaiyah
authors.initials: K
authors.lastname: Selvendiran
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology;
authors.forename: Kellie S
authors.initials: KS
authors.lastname: Rath
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center;
authors.forename: Shun
authors.initials: S
authors.lastname: He
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Bailey
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: David
authors.initials: D
authors.lastname: Eaves
authors.affiliation: Department of Pediatrics, Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and the Division of Hematology/Oncology/BMT, Nationwide Children's Hospital;
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
authors.affiliation: Department of Molecular Virology Immunology Medical Genetics, The Ohio State University, Columbus; and.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Parris
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center;
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery; Balveen.Kaur@osumc.edu matthew.old@osumc.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Old
authors.affiliation: Authors' Affiliations: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences; Balveen.Kaur@osumc.edu matthew.old@osumc.edu.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005260:Female; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D008819:Mice, Nude; D009336:Necrosis; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D011719:Pyrazines / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D011719:Pyrazines; D000069286:Bortezomib