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Cancer Chemother Pharmacol (2009) 63:723730
DOI 10.1007/s00280-008-0791-x
ORIGINAL ARTICLE
Targeting superoxide dismutase 1 to overcome cisplatin resistance in human ovarian cancer
Dawn P. G. Brown Helen Chin-Sinex Bei Nie Marc S. Mendonca Mu Wang
Received: 16 March 2008 / Accepted: 17 June 2008 / Published online: 12 July 2008 Springer-Verlag 2008
Abstract
Purpose Clinical drug resistance to platinum-based chemotherapy is considered a major impediment in the treatment of human ovarian cancer. Multiple pathways associated with drug resistance have been suggested by many previous studies. Over expression of several key proteins involved in DNA repair, drug transport, redox regulation, and apoptosis has been recently reported by our group using a global quantitative proteomic proWling approach. Superoxide dismutase 1 (SOD1) is one of these proteins consistently over-expressed in cisplatin-resistant ovarian cancer cells as compared to their sensitive counterparts, but its precise role in drug resistance is yet to be deWned. Method In the current study, we examined the role of SOD1 in drug resistance by inhibiting its redox activity in
cisplatin-resistant ovarian cancer cells using a small-molecule inhibitor, triethylenetetramine (TETA). The eVect of TETA was determined by the cell proliferation assay, clonogenic cell survival assay, and SOD1 activity assay. Results The inhibition of the SOD1 activity enhanced the cisplatin sensitivity in the resistant cells supporting the hypothesis that SOD1 is a key determinant of cisplatin resistance and is an exploitable target to overcome cisplatin drug resistance.
Conclusion SOD1 plays an important role in cisplatin resistance and modulation of its activity may overcome this resistance and ultimately lead to improved clinical outcomes.
Keywords Ovarian cancer Cisplatin resistance Superoxide dismutase 1 Reactive oxygen species Mass spectrometry
Abbreviations
ACN AcetonitrileCDDP Cisplatin or cis-diaminedichloroplatinum MS Mass spectrometryROS Reactive oxygen speciesSOD1 Superoxide dismutase 1SRM Selected-reaction-monitoringTETA Triethylenetetramine
Introduction
Today ovarian cancer is the fourth leading cause of death from cancer in women [1]. New and improved therapeutic treatment has been a target of much research [1, 2]. Cisplatin is one of the most eVective and commonly used chemotherapeutic agents in the treatment of ovarian cancer [3]. It is believed that cisplatin-induced cell death is a result of
D. P. G. Brown B. Nie M. WangDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
H. Chin-Sinex M. S....