A Redox-active Mn Porphyrin, MnTnBuOE-2-PyP5+, Synergizes with Carboplatin in Treatment of Chemoresistant Ovarian Cell Line

Author:

Chaiswing Luksana1ORCID,Yarana Chontida2,St. Clair William3,Tovmasyan Artak4ORCID,Batinic-Haberle Ines5ORCID,Spasojevic Ivan67ORCID,St. Clair Daret1

Affiliation:

1. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA

2. Faculty of Medical Technology, Mahidol University, Thailand

3. Department of Radiation Oncology, University of Kentucky, Kentucky, USA

4. Translational Neuroscience at Barrow Neurological Institute, AZ, USA

5. Department of Radiation Oncology, Duke University, USA

6. Department of Medicine, Duke University School of Medicine, Durham, NC, USA

7. Pharmacokinetics/Pharmacodynamics Core Laboratory, Duke University School of Medicine, Durham, NC, USA

Abstract

We have employed a redox-active MnP (MnTnBuOE-2-PyP5+, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX-001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy-resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (H2O2) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90). Our goal was to study how ovarian cell growth depends upon the redox state of the cell; hence, we used MnP (BMX-001), a redox-active MnSOD mimetic, as a molecular tool to alter ovarian cancer redox state. Interestingly, OVCD cells preferentially uptake MnP relative to OV90 cells which led to increased inhibition of cell growth, glycolytic activity, OXPHOS, and ATP, in OVCD cells. These effects were further increased when MnP was combined with carboplatin. The effects were discussed with regard to the elevation in H2O2 levels, increased oxidative stress, and reduced Nrf2 levels and its downstream targets when cells were exposed to either MnP or MnP/carboplatin. It is significant to emphasize that MnP protects normal ovarian cell line, hTER7, against carboplatin toxicity. Our data demonstrate that the addition of MnP-based redox-active drugs may be used (via increasing excessively the oxidative stress of serous ovarian cancer cells) to improve cancer patients’ chemotherapy outcomes, which develop resistance to platinum-based drugs.

Funder

NCI Comprehensive Cancer Center Core

Publisher

Hindawi Limited

Subject

Cell Biology,Aging,General Medicine,Biochemistry

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