title: Reolysin is a novel reovirus-based agent that induces endoplasmic reticular stress-mediated apoptosis in pancreatic cancer.
abstract: Activating mutation of KRas is a genetic alteration that occurs in the majority of pancreatic tumors and is therefore an ideal therapeutic target. The ability of reoviruses to preferentially replicate and induce cell death in transformed cells that express activated Ras prompted the development of a reovirus-based formulation for cancer therapy called Reolysin. We hypothesized that Reolysin exposure would trigger heavy production of viral products leading to endoplasmic reticular (ER) stress-mediated apoptosis. Here, we report that Reolysin treatment stimulated selective reovirus replication and decreased cell viability in KRas-transformed immortalized human pancreatic duct epithelial cells and pancreatic cancer cell lines. These effects were associated with increased expression of ER stress-related genes, ER swelling, cleavage of caspase-4, and splicing of XBP-1. Treatment with ER stress stimuli including tunicamycin, brefeldin A, and bortezomib (BZ) augmented the anticancer activity of Reolysin. Cotreatment with BZ and Reolysin induced the simultaneous accumulation of ubiquitinated and viral proteins, resulting in enhanced levels of ER stress and apoptosis in both in vitro and in vivo models of pancreatic cancer. Our collective results demonstrate that the abnormal protein accumulation induced by the combination of Reolysin and BZ promotes heightened ER stress and apoptosis in pancreatic cancer cells and provides the rationale for a phase I clinical trial further investigating the safety and efficacy of this novel strategy.
authors.affiliation: Department of Medicine, Cancer Therapy and Research Center, Institute for Drug Development, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Carew
authors.forename: C M
authors.initials: CM
authors.lastname: Espitia
authors.forename: W
authors.initials: W
authors.lastname: Zhao
authors.forename: K R
authors.initials: KR
authors.lastname: Kelly
authors.forename: M
authors.initials: M
authors.lastname: Coffey
authors.forename: J W
authors.initials: JW
authors.lastname: Freeman
authors.forename: S T
authors.initials: ST
authors.lastname: Nawrocki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D020126:Brefeldin A / Q000494:pharmacology; D053471:Caspases, Initiator / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003131:Combined Modality Therapy; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D030102:Orthoreovirus, Mammalian / Q000235:genetics* / Q000502:physiology; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011719:Pyrazines / Q000494:pharmacology; D012087:Reoviridae; D014415:Tunicamycin / Q000494:pharmacology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D014415:Tunicamycin; D020126:Brefeldin A; D000069286:Bortezomib; C093516:CASP4 protein, human; D053471:Caspases, Initiator; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins