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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA182804-01
Application #
8623548
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Arya, Suresh
Project Start
2013-12-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$338,391
Indirect Cost
$114,291
Name
University of Iowa
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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