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Targeting superoxide dismutase 1 to overcome cisplatin resistance in human ovarian cancer

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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 profiling 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 defined.

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 effect 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.

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Abbreviations

ACN:

Acetonitrile

CDDP:

Cisplatin or cis-diaminedichloroplatinum

MS:

Mass spectrometry

ROS:

Reactive oxygen species

SOD1:

Superoxide dismutase 1

SRM:

Selected-reaction-monitoring

TETA:

Triethylenetetramine

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Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Dawn P. G. Brown, Bei Nie & Mu Wang

  2. Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Helen Chin-Sinex & Marc S. Mendonca

  3. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Marc S. Mendonca

  4. Monarch LifeSciences, Indianapolis, IN, 46202, USA

    Mu Wang

  5. Indiana University Biotechnology Research and Training Center, 1345 W. 16th Street, Rm 312, Indianapolis, IN, 46202, USA

    Mu Wang

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  1. Dawn P. G. Brown
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Correspondence to Mu Wang.

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Brown, D.P.G., Chin-Sinex, H., Nie, B. et al. Targeting superoxide dismutase 1 to overcome cisplatin resistance in human ovarian cancer. Cancer Chemother Pharmacol 63, 723–730 (2009). https://doi.org/10.1007/s00280-008-0791-x

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  • DOI: https://doi.org/10.1007/s00280-008-0791-x

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