Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells
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University of Cincinnati / OhioLINK
2017
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin15118807062705212021-08-03T07:04:45Z Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells Abdul Salam, Safnas Farwin Biochemistry ROS Anticancer agents antioxidant oxidative stress DNA damage oxazolone 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. 2017 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511880706270521 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511880706270521 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biochemistry ROS Anticancer agents antioxidant oxidative stress DNA damage oxazolone |
| spellingShingle |
Biochemistry ROS Anticancer agents antioxidant oxidative stress DNA damage oxazolone Abdul Salam, Safnas Farwin Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells |
| author |
Abdul Salam, Safnas Farwin |
| author_facet |
Abdul Salam, Safnas Farwin |
| author_sort |
Abdul Salam, Safnas Farwin |
| title |
Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells |
| title_short |
Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells |
| title_full |
Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells |
| title_fullStr |
Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells |
| title_full_unstemmed |
Biochemistry of Reactive Oxygen Species in Selective Cancer Cell Toxicity and Protection of Normal Cells |
| title_sort |
biochemistry of reactive oxygen species in selective cancer cell toxicity and protection of normal cells |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2017 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511880706270521 |
| work_keys_str_mv |
AT abdulsalamsafnasfarwin biochemistryofreactiveoxygenspeciesinselectivecancercelltoxicityandprotectionofnormalcells |
| _version_ |
1719453226443472896 |