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Targeting the Stress Response to ROS: Design and Development of Novel and Selective Anti-cancer Agents

Kizhakkekkara Vadukoot, Anish
http://orcid.org/0000-0001-7063-0479
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460652535

Abstract Details

2016, PhD, University of Cincinnati, Arts and Sciences: Chemistry.
Cancer is defined as abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize. Cancer can be initiated by various factors working alone or in combination. Some cancers are caused by external factors such as tobacco, diet, certain chemicals, radiation, and viruses while other cancers are caused by internal factors such as hormones, immune conditions, and inherited genetic mutations. Damage to DNA by reactive oxygen species (ROS) is widely accepted as a major cause of cancer. ROS are chemically reactive molecules formed as a natural byproduct of metabolism in cells. These species play an important role in cell signaling and homeostasis. ROS levels are kept under control by cellular antioxidant systems. Whenever there is an imbalance in ROS generation ad its regulation, it leads to oxidative stress. Elevated levels of ROS have been detected in different types of cancer cells where they are known to promote tumor progression and survival including renal cell carcinoma, melanoma, and leukemia. These ROS levels are higher when compared to normal cells. This high ROS levels in cancer cells makes them susceptible to oxidative stress induced cell death and can be exploited for development of selective anticancer therapy. Many chemotherapeutic strategies are designed to increase cellular ROS levels to induce irreparable damages to cell leading to apoptosis. This can be achieved by using compounds that inhibit antioxidant systems or through inhibition of specific signaling pathways that upregulate antioxidants in cancer cells. The resulting increase in ROS may induce tumor cell death either through damaging functions of ROS like DNA oxidation, lipid peroxidation or by specific initiation of apoptosis via death signaling pathways. As basal ROS levels in normal cells are comparatively low, these cells are not significantly affected leading to selectivity in chemotherapy. My work focuses on design and development of novel anticancer agents that are ROS activated. These are stable prodrugs which are activated only in the presence of ROS. Upon activation they tend to form a potent electrophile which can react with cellular nucleophiles such as DNA or cellular antioxidants causing their inactivation leading to ROS imbalance and ultimately triggering apoptosis.
Edward Merino, Ph.D. (Committee Chair)
Michael Baldwin, Ph.D. (Committee Member)
James Mack, Ph.D. (Committee Member)
161 p.
Organic Chemistry
ROS; Cancer; Chemotherapy; Prodrugs; DNA alkylating agents; Acute Myeloid Leukemia

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Citations

  • Kizhakkekkara Vadukoot, A. (2016). Targeting the Stress Response to ROS: Design and Development of Novel and Selective Anti-cancer Agents [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460652535

    APA Style (7th edition)

  • Kizhakkekkara Vadukoot, Anish. Targeting the Stress Response to ROS: Design and Development of Novel and Selective Anti-cancer Agents. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460652535.

    MLA Style (8th edition)

  • Kizhakkekkara Vadukoot, Anish. "Targeting the Stress Response to ROS: Design and Development of Novel and Selective Anti-cancer Agents." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460652535

    Chicago Manual of Style (17th edition)

ucin1460652535
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This open access ETD is published by University of Cincinnati and OhioLINK.