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Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells

Abdul Salam, Safnas Farwin
http://orcid.org/0000-0001-5727-2873
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511880706270521

Abstract Details

2017, PhD, University of Cincinnati, Arts and Sciences: Chemistry.
Reactive oxygen species (ROS), includes highly reactive molecules and radicals, derived from metabolism of molecular oxygen, and have important roles in cellular signaling. At high concentrations, ROS reacts with cellular macromolecules and leads to a stress condition known as oxidative stress. Several cancer cells, such as AML cancers exhibit high ROS levels to facilitate growth and adaptation signaling. Thus, this characteristic could be used for selective targeting of cancer cells. We use ROS to selectively activate reactive anticancer agents in AML cells with high ROS status. Structure activity relationship identifies a lead agent (RAP) that has 2 µM IC50 value and more than 10-fold selectivity towards AML cancer cells compared to normal blood stem cells. We show that the agent is reactive within cells and induces an electrophilic stress condition. Importantly, further studies identify that this agent targets cancer cells with high mitochondrial ROS generation. Mitochondrial metabolism of cancer cells as an anti-cancer liability, is gaining attention in recent literature. We show that the AML cells that are targeted by RAP, have high mitochondrial activity and exposure to RAP results in damage of mitochondria, and oxidative cell death. Further, RAP activity synergizes with anti-diabetic agent Metformin and natural molecule Rotenone, which exhibit anticancer properties by targeting mitochondria. Inhibition of mitochondrial complexes by agents like Metformin, lead to increased ROS leakage from mitochondria that enhances the activation of RAP. This further proves the suggested mechanism of RAP, while paving the way for future drug combination studies. The next part of this dissertation focuses on designing efficient antioxidant agents by altering the structure of RAP, in order to protect normal cells from oxidative stress mediated cell death. Though antioxidant therapy is promising strategy to treat oxidative stress caused by several disease conditions or toxin exposure, many antioxidants fail in clinical trials, mostly due to lack of selectivity to potent ROS and limited solubility. We show that RAP undergoes six electron oxidation mechanism upon exposure to hydroxyl radical generating Fenton condition. A class of stable and efficient antioxidants are designed by altering the structure of RAP. The agents are designed to selectively react with toxic ROS species, such as hydroxyl radical thus preventing DNA damage, in cells. By using ROS elevating environmental toxin Arsenic trioxide, I identified a lead antioxidant agent (1c) that prevents cell death of fibroblast cells exposed to arsenic trioxide. Further we show that 1c prevents ROS elevation and formation of mutant oxidative DNA lesion oxazolone, in normal skin fibroblast cells, that are exposed to arsenic trioxide.
Edward Merino, Ph.D. (Committee Chair)
Neil Ayres, Ph.D. (Committee Member)
Pearl Tsang, Ph.D. (Committee Member)
126 p.
Biochemistry
ROS; Anticancer agents; antioxidant; oxidative stress; DNA damage; oxazolone

Recommended Citations

Citations

  • Abdul Salam, S. F. (2017). Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511880706270521

    APA Style (7th edition)

  • Abdul Salam, Safnas Farwin. Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511880706270521.

    MLA Style (8th edition)

  • Abdul Salam, Safnas Farwin. "Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511880706270521

    Chicago Manual of Style (17th edition)

ucin1511880706270521
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This open access ETD is published by University of Cincinnati and OhioLINK.