NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by dep
- PDF / 1,415,324 Bytes
- 12 Pages / 610 x 792 pts Page_size
- 38 Downloads / 170 Views
BioMed Central
Open Access
Research
NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols Anna Bratasz1, Karuppaiyah Selvendiran1, Tomasz Wasowicz1, Andrey Bobko1, Valery V Khramtsov1, Louis J Ignarro2 and Periannan Kuppusamy*1,3 Address: 1Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA, 2Department of Molecular and Medical Pharmacology, Center for the Health Sciences, University of California School of Medicine, Los Angeles, CA 90095, USA and 3Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA Email: Anna Bratasz - [email protected]; Karuppaiyah Selvendiran - [email protected]; Tomasz Wasowicz - [email protected]; Andrey Bobko - [email protected]; Valery V Khramtsov - [email protected]; Louis J Ignarro - [email protected]; Periannan Kuppusamy* - [email protected] * Corresponding author
Published: 26 February 2008 Journal of Translational Medicine 2008, 6:9
doi:10.1186/1479-5876-6-9
Received: 17 November 2007 Accepted: 26 February 2008
This article is available from: http://www.translational-medicine.com/content/6/1/9 © 2008 Bratasz et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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-4040treated A2780 cDDP tumors when compared to untreated controls. Imm
Data Loading...
