Abstract
Abstract 3527: Inhibition of mitochondrial pyruvate transport selectively sensitizes cancer cells to metabolic oxidative stress
Cancer research (Chicago, Ill.), Vol.78(13_Supplement), pp.3527-3527
07/01/2018
DOI: 10.1158/1538-7445.AM2018-3527
Abstract
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. Supported by R01CA182804. Citation Format: Shane R. Solst, Samuel N. Rodman, Melissa A. Fath, Eric B. Taylor, Douglas R. Spitz. Inhibition of mitochondrial pyruvate transport selectively sensitizes cancer cells to metabolic oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3527.
Details
- Title: Subtitle
- Abstract 3527: Inhibition of mitochondrial pyruvate transport selectively sensitizes cancer cells to metabolic oxidative stress
- Creators
- Shane R. SolstSamuel N. RodmanMelissa A. FathEric B. TaylorDouglas R. Spitz
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.78(13_Supplement), pp.3527-3527
- DOI
- 10.1158/1538-7445.AM2018-3527
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 07/01/2018
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Fraternal Order of Eagles Diabetes Research Center; Radiation Oncology
- Record Identifier
- 9984314291902771
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