title: Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer.
abstract: This study examines the role of s-nitrosylation in the growth of ovarian cancer using cell culture based and in vivo approaches. Using the nitrosylating agent, S-nitrosoglutathione (GSNO), a physiological nitric oxide molecule, we show that GSNO treatment inhibited proliferation of chemoresponsive and chemoresistant ovarian cancer cell lines (A2780, C200, SKVO3, ID8, OVCAR3, OVCAR4, OVCAR5, OVCAR7, OVCAR8, OVCAR10, PE01 and PE04) in a dose dependent manner. GSNO treatment abrogated growth factor (HB-EGF) induced signal transduction including phosphorylation of Akt, p42/44 and STAT3, which are known to play critical roles in ovarian cancer growth and progression. To examine the therapeutic potential of GSNO in vivo, nude mice bearing intra-peritoneal xenografts of human A2780 ovarian carcinoma cell line (2 × 10(6)) were orally administered GSNO at the dose of 1 mg/kg body weight. Daily oral administration of GSNO significantly attenuated tumor mass (p<0.001) in the peritoneal cavity compared to vehicle (phosphate buffered saline) treated group at 4 weeks. GSNO also potentiated cisplatin mediated tumor toxicity in an A2780 ovarian carcinoma nude mouse model. GSNO's nitrosylating ability was reflected in the induced nitrosylation of various known proteins including NFκB p65, Akt and EGFR. As a novel finding, we observed that GSNO also induced nitrosylation with inverse relationship at tyrosine 705 phosphorylation of STAT3, an established player in chemoresistance and cell proliferation in ovarian cancer and in cancer in general. Overall, our study underlines the significance of S-nitrosylation of key cancer promoting proteins in modulating ovarian cancer and proposes the therapeutic potential of nitrosylating agents (like GSNO) for the treatment of ovarian cancer alone or in combination with chemotherapeutic drugs.
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Giri
authors.affiliation: Women's Health Services, Henry Ford Health System, Detroit, Michigan, United States of America.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Rattan
authors.affiliation: Department of Neurology, Henry Ford Health system, Detroit, Michigan, United States of America.
authors.forename: Mandar
authors.initials: M
authors.lastname: Deshpande
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Jacie L
authors.initials: JL
authors.lastname: Maguire
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Johnson
authors.affiliation: Department of Anatomic/Clinical Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Rondell P
authors.initials: RP
authors.lastname: Graham
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001710:Biotin / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D015538:Nitrosation / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D026422:S-Nitrosoglutathione / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D050796:STAT3 Transcription Factor; D026422:S-Nitrosoglutathione; D001710:Biotin; D004247:DNA; D002945:Cisplatin