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NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols

Please use this identifier to cite or link to this item: http://hdl.handle.net/1811/47350

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dc.creator Bratasz, Anna
dc.creator Selvendiran, Karuppaiyah
dc.creator Wasowicz, Tomasz
dc.creator Bobko, Andrey
dc.creator Khramtsov, Valery V.
dc.creator Ignarro, Louis J.
dc.creator Kuppusamy, Periannan
dc.date.accessioned 2010-12-07T16:38:26Z
dc.date.available 2010-12-07T16:38:26Z
dc.date.issued 2008-02-26
dc.identifier.citation Anna Bratasz et al, "NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols," Journal of Translational Medicine 6 (2008), doi:10.1186/1479-5876-6-9, http://www.translational-medicine.com/content/6/1/9 en_US
dc.identifier.issn 1479-5876
dc.identifier.uri http://hdl.handle.net/1811/47350
dc.description.abstract Background: Ovarian carcinoma is the leading cause of mortality among gynecological cancers in the world. The high mortality rate is associated with lack of early diagnosis and development of drug resistance. The antitumor efficacy and mechanism of NCX-4040, a nitric oxide-releasing aspirin derivative, against ovarian cancer is studied. Methods: NCX-4040, alone or in combination with cisplatin (cis-diamminedichloroplatinum, cDDP), was studied in cisplatin-sensitive (A2780 WT) and cisplatin-resistant (A2780 cDDP) cell lines as well as xenograft tumors grown in nude mice. Electron paramagnetic resonance (EPR) was used for measurements of nitric oxide and redox state. Immunoblotting analysis of A2780 cDDP tumor xenografts from mice was used for mechanistic studies. Results: Cells treated with NCX-4040 (25 μM) showed a significant reduction of cell viability (A2780 WT, 34.9 ± 8.7%; A2780 cDDP, 41.7 ± 7.6%; p < 0.05). Further, NCX-4040 significantly enhanced the sensitivity of A2780 cDDP cells (cisplatin alone, 80.6 ± 11.8% versus NCX-4040+cisplatin, 26.4 ± 7.6%; p < 0.01) and xenograft tumors (cisplatin alone, 74.0 ± 4.4% versus NCX-4040+cisplatin, 56.4 ± 7.8%; p < 0.05), to cisplatin treatment. EPR imaging of tissue redox and thiol measurements showed a 5.5-fold reduction (p < 0.01) of glutathione in NCX-4040- treated A2780 cDDP tumors when compared to untreated controls. Immunoblotting analysis of A2780 cDDP tumor xenografts from mice treated with NCX-4040 and cisplatin revealed significant downregulation of pEGFR (Tyr845 and Tyr992) and pSTAT3 (Tyr705 and Ser727) expression. Conclusion: The results suggested that NCX-4040 could resensitize drug-resistant ovarian cancer cells to cisplatin possibly by depletion of cellular thiols. Thus NCX-4040 appears to be a potential therapeutic agent for the treatment of human ovarian carcinoma and cisplatin-resistant malignancies. en_US
dc.language.iso en_US en_US
dc.publisher BioMed Central en_US
dc.title NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols en_US
dc.type Article en_US
dc.identifier.doi 10.1186/1479-5876-6-9
dc.identifier.osuauthor bratasz.1
dc.identifier.osuauthor bobko.3
dc.identifier.osuauthor khramtsov.1
dc.identifier.osuauthor kuppusamy.1
dc.rights.cc Attribution 3.0 Unported en_US
dc.rights.ccuri http://creativecommons.org/licenses/by/3.0/ en_US
Attribution 3.0 Unported This item is licensed under a Creative Commons License:
Attribution 3.0 Unported