Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer

Shailendra Giri, Ramandeep Rattan, Mandar Deshpande, Jacie L. Maguire, Zachary Johnson, Rondell Graham, Vijayalakshmi Shridhar

Research output: Contribution to journalArticle

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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 (2×106) 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 NFkB 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.

Original languageEnglish (US)
Article numbere97897
JournalPLoS One
Volume9
Issue number6
DOIs
StatePublished - Jun 2 2014

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Phosphorylation
ovarian neoplasms
Ovarian Neoplasms
Tumors
Bearings (structural)
Cells
S-Nitrosoglutathione
Signal transduction
therapeutics
Cell proliferation
Cell culture
Heterografts
Cisplatin
Toxicity
Tyrosine
Intercellular Signaling Peptides and Proteins
Nitric Oxide
Proteins
neoplasms
Phosphates

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer. / Giri, Shailendra; Rattan, Ramandeep; Deshpande, Mandar; Maguire, Jacie L.; Johnson, Zachary; Graham, Rondell; Shridhar, Vijayalakshmi.

In: PLoS One, Vol. 9, No. 6, e97897, 02.06.2014.

Research output: Contribution to journalArticle

Giri, Shailendra ; Rattan, Ramandeep ; Deshpande, Mandar ; Maguire, Jacie L. ; Johnson, Zachary ; Graham, Rondell ; Shridhar, Vijayalakshmi. / Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer. In: PLoS One. 2014 ; Vol. 9, No. 6.
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