The role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer.
OBJECTIVE
To investigate the role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer (EOC).


METHODS
Two parent EOC cell lines (MDAH-2774 and SKOV-3) and their chemoresistant counterparts (cisplatin, 50 µmol/L) were used. Total RNA was extracted and subjected to real-time reverse transcriptase polymerase chain reaction to evaluate the expression of glutathione reductase (GSR) and inducible nitric oxide synthase (iNOS), as well as nitrate/nitrite levels. Analysis of variance was used for main effects and Tukey for post hoc analysis at P < .05 for statistical significance.


RESULTS
Both cisplatin resistant cell lines displayed a significant decrease in GSR messenger RNA (mRNA) levels and activity (P < .01). As compared to sensitive controls, nitrate/nitrite levels were significantly higher in SKOV-3 cisplatin resistant cells while iNOS mRNA levels were significantly higher in MDAH-2774 cisplatin resistant cells (P < .05).


CONCLUSIONS
Our data suggest that the development of cisplatin resistance tilts the balance toward a pro-oxidant state in EOC.
1Department of Obstetrics and Gynecology, C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA.
Jimmy
J
Belotte
Nicole M
NM
Fletcher
Awoniyi O
AO
Awonuga
Mitchell
M
Alexis
Husam M
HM
Abu-Soud
Mohammed G
MG
Saed
Michael P
MP
Diamond
Ghassan M
GM
Saed
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism
D000970:Antineoplastic Agents; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D005980:Glutathione Reductase; D002945:Cisplatin
cisplatin resistance; epithelial ovarian cancer; reactive oxygen species