Abstract
141 - Inhibition of Mitochondrial Pyruvate Transport Selectively Sensitizes Cancer Cells to Metabolic Oxidative Stress
Free radical biology & medicine, Vol.112, pp.102-102
11/2017
DOI: 10.1016/j.freeradbiomed.2017.10.154
Abstract
To determine if mitochondrial pyruvate transport could represent a therapeutic target for sensitizing cancer cells to oxidative stress, lung and breast cancer cells were treated with 5 µM UK5099 to inhibit the mitochondrial pyruvate carrier (MPC). Treatment with UK5099 selectively sensitized lung and breast cancer cells to clonogenic cell killing when combined with depletion of glutathione using 1 mM buthionine sulfoximine (BSO; a glutathione synthesis inhibitor) for 48 h and 72 h, relative to normal lung and breast epithelial cells. Furthermore, cancer cell killing mediated by UK5099 combined with BSO was inhibited by the thiol antioxidant, N-acetylcysteine (NAC; 20 mM), independent of GSH levels indicating a mechanism of toxicity involving reduced thiols and metabolic oxidative stress. In addition, treatment with UK5099 alone for 48 h also decreased levels of total glutathione in cancer cells that could be reversed by NAC. Using oxidation sensitive fluorescent dyes (CDCFH2 and MitoSOX), treatment of lung and breast cancer cells for 24 h and 48 h with UK5099 induced increases in steady state levels of pro-oxidants (presumably hydroperoxides and mitochondrial superoxide) which were further increased with BSO. Finally, treatment of breast cancer cells with UK5099 for 24 and 48 hours significantly sensitized breast cancer cells to clonogenic cell killing mediated by paclitaxel. These data support the hypothesis that inhibition of the MPC selectively causes an impairment of antioxidant capability in cancer cells that is enhanced by depletion of glutathione. Furthermore, these results also support the hypothesis that inhibition of the MPC represents a significant target for sensitizing human breast cancer cells to chemotherapy agents thought to induce oxidative stress.
Details
- Title: Subtitle
- 141 - Inhibition of Mitochondrial Pyruvate Transport Selectively Sensitizes Cancer Cells to Metabolic Oxidative Stress
- Creators
- Shane R Solst - University of IowaSamuel N Rodman - University of IowaMelissa A Fath - University of IowaEric B Taylor - University of IowaDouglas R Spitz - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Free radical biology & medicine, Vol.112, pp.102-102
- DOI
- 10.1016/j.freeradbiomed.2017.10.154
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 11/2017
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984314296302771
Metrics
17 Record Views