The development of modern cancer therapies is predicated on the idea that anticancer agents should selectively kill cancer vs. normal cells by exploiting biochemical and physiological differences specific to cancer cells. The notion that early progenitor "cancer stem cells" (CSCs) may represent a subpopulation of cancer cells contributing to treatment failure has also gained significant experimental support. Furthermore, fundamental differences in oxidative metabolism between cancer and normal cells appear to lead to increased steady-state levels of reactive oxygen species (ROS;O2.- and H2O2) and may represent a "target" for selectively enhancing therapeutic responses. If survival of CSCs could be compromised by selectively enhancing the production of ROS while inhibiting hydroperoxide metabolism, then differences in CSC metabolism could be exploited to selectively improve responses to conventional radio-chemo-therapies. Preliminary data shows that early progenitor CSCs from human breast carcinoma population exhibit increased steady-state levels of O2?- relative to stem cells derived from normal breast epithelial cell populations. In addition, pharmacological manipulations of ROS levels [with mitochondrial targeted triphenylphosphonium derivatives;TPP] and/or inhibition of glutathione (GSH)- and thioredoxin (Trx)- dependent hydroperoxide metabolism [using buthionine sulfoximine (BSO) and Auranofin (AUR)] is shown to selectively deplete CSCs, relative to normal stem cells by inducing metabolic oxidative stress. Finally, TPP derivatives are well tolerated in animals and simultaneous inhibition of GSH- and Trx-dependent hydroperoxide metabolism (AUR+BSO) enhances CSCs responses to radiation. These preliminary data led to the hypothesis that pharmacological manipulations designed to increase mitochondrial ROS production (with TPP derivatives) combined with inhibitors of GSH- and Trx- dependent hydroperoxide metabolism will cause selective cytotoxicity in CSCs (vs. normal stem cells) as well as enhance tumor responses to radio-chemo-therapies by increasing O2?- and H2O2-mediated oxidative stress. This hypothesis will be tested in two Aims to: 1) Determine if pharmacological manipulations with TPP derivatives will selectively enhance oxidative stress as well as chemo-radio-sensitivity by increasing mitochondrial O2?- and H2O2 in cancer vs. normal stem cells in vitro and in vivo and 2) Determine if simultaneous inhibition of GSH- and Trx-dependent hydroperoxide metabolism combined with TPP derivatives can selectively sensitize cancer vs. normal stem cells to chemo- or radio-sensitivity by increasing O2?- and H2O2-mediated oxidative stress. Completing these studies will provide a detailed mechanistic understanding of the potential for using manipulations of mitochondrial ROS in combination with inhibitors of hydroperoxide metabolism to selectively kill cancer stem cells. This work addresses a critical question in cancer biology necessary for exploiting altered stem cell oxidative metabolism to enhance cancer therapy.
The development of modern cancer therapies is predicated on the idea that anticancer agents should selectively kill cancer vs. normal cells by exploiting biochemical and physiological differences specific to cancer cells. The current application will determine if alterations in mitochondrial oxidative metabolism can be exploited to enhance therapeutic responses to radio-chemo-therapy in cancer vs. normal stem cells to selectively inhibit cancer stem cell survival. Successful completion of these studies will provide a detailed mechanistic understanding of how to use pharmacological agents that exploit altered cancer vs. normal stem cell oxidative metabolism to selectively enhance responses to conventional radio-chemo-therapies.
|Klaren, William D; Gibson-Corley, Katherine N; Wels, Brian et al. (2016) Assessment of the Mitigative Capacity of Dietary Zinc on PCB126 Hepatotoxicity and the Contribution of Zinc to Toxicity. Chem Res Toxicol 29:851-9|
|Rodman, Samuel N; Spence, Jacquelyn M; Ronnfeldt, Tyler J et al. (2016) Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism. Radiat Res 186:385-395|
|Hrabe, Jennifer E; O'Leary, Brianne R; Fath, Melissa A et al. (2015) Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor Î²-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells. Redox Biol 5:319-27|
|Du, Juan; Cieslak 3rd, John A; Welsh, Jessemae L et al. (2015) Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer. Cancer Res 75:3314-26|
|O'Leary, Brianne R; Fath, Melissa A; Bellizzi, Andrew M et al. (2015) Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 21:1741-51|
|Rasmussen, Tyler P; Wu, Yuejin; Joiner, Mei-ling A et al. (2015) Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. Proc Natl Acad Sci U S A 112:9129-34|
|Li, Ling; Fath, Melissa A; Scarbrough, Peter M et al. (2015) Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer. Redox Biol 4:127-35|
|Bayer, Jennifer L; Spitz, Douglas R; Christensen, Desire et al. (2015) Biobehavioral and neuroendocrine correlates of antioxidant enzyme activity in ovarian carcinoma. Brain Behav Immun 50:58-62|
|Allen, Bryan G; Bhatia, Sudershan K; Anderson, Carryn M et al. (2014) Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biol 2:963-70|
|Wegman-Points, Lauren J; Teoh-Fitzgerald, Melissa L T; Mao, Gaowei et al. (2014) Retroviral-infection increases tumorigenic potential of MDA-MB-231 breast carcinoma cells by expanding an aldehyde dehydrogenase (ALDH1) positive stem-cell like population. Redox Biol 2:847-54|
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