title: Targeting Survivin Enhances Chemosensitivity in Retinoblastoma Cells and Orthotopic Tumors.
abstract: Treatments for retinoblastoma (Rb) vary depending on the size and location of the intraocular lesions and include chemotherapy and radiation therapy. We examined whether agents used to treat Rb induce a pro-survival phenotype associated with increased expression of survivin, a member of the inhibitor of apoptosis family of proteins. We document that exposure to carboplatin, topotecan or radiation resulted in elevated expression of survivin in two human Rb cell lines but not in normal retinal pigmented epithelial (RPE) cells. Cellular levels of survivin were attenuated in Rb cells exposed to an imidazolium-based survivin suppressant, Sepantronium bromide (YM155). Protein expression patterns of survivin in RPE cells were not altered following treatment protocols involving exposure to YM155. Including YM155 with chemotherapy or radiation increased levels of apoptosis in Rb cells but not in RPE cells. Intraocular luciferase expressing Rb tumors were generated from the Rb cell lines and used to evaluate the effects of carboplatin and YM155 on in-vivo survivin expression and tumor growth. Carboplatin induced expression of survivin while carboplatin combined with YM155 reduced survivin expression in tumor bearing eyes. The combination protocol was also most effective in reducing the rate of tumor regrowth. These results indicate that targeted inhibition of the anti-apoptotic protein survivin provides a therapeutic advantage for Rb cells and tumors treated with chemotherapy.
authors.affiliation: The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, 90027, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Ferrario
authors.affiliation: The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, 90027, United States of America.
authors.forename: Marian
authors.initials: M
authors.lastname: Luna
authors.affiliation: The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, 90027, United States of America.
authors.forename: Natalie
authors.initials: N
authors.lastname: Rucker
authors.affiliation: The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, 90027, United States of America.
authors.forename: Sam
authors.initials: S
authors.lastname: Wong
authors.affiliation: The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, 90027, United States of America.
authors.forename: Ariel
authors.initials: A
authors.lastname: Lederman
authors.affiliation: The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, 90027, United States of America.|Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, 90027, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kim
authors.affiliation: The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, 90027, United States of America.|Departments of Pediatrics and Radiation Oncology, Keck School of Medicine, University of Southern California, Los Angeles, California, 90027, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Gomer
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D012175:Retinoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin