Anticancer potential of nitric oxide-based therapeutics for pediatric and adult cancers
Date
2021
Authors
Gordon, Jenna Leigh, author
Reynolds, Melissa, advisor
Henry, Chuck, committee member
Kennan, Alan, committee member
Brown, Mark, committee member
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Abstract
Based on 2015-2017 data, nearly 40% of men and women will be diagnosed with cancer at some point throughout their lives. As a worldwide pandemic, cancer presents a colossal challenge for researchers and clinicians to continually develop and implement new strategies to prevent, diagnose, and treat the many variations of this disease. Currently, treatment protocols are dominated by surgery, chemotherapy, and radiation therapy. Although valuable, these treatments are often ineffective and are limited to specific situations. Surgery is typically useful for early-stage cancer treatment while chemotherapy and radiation therapy are more common for late-stage treatment. Chemotherapy and radiation therapies are subject to drug resistance and all three produce patient side effects. Thus, a persistent need to develop drugs that are more effective, preferential (to neoplastic cells), and accessible remains. This work implements therapeutics that addresses those concerns while demonstrating efficacy within both pediatric and adult cancers. An evaluation of the anticancer potential of nitric oxide (NO) releasing S-nitrosothiol based anticancer therapeutics is presented herein. In the determination of clinical translatability of a drug, it is essential to understand the desired outcome and potential sources of error prior to execution of analyses and the corresponding methodologies and measurements. Thus, an in-depth analysis of indicators for therapeutic efficacy using tumor-derived cell lines and a detailed investigation of the protocol development and potential interferences of three common cellular viability assays is presented prior to the in vitro work detailed in this study. Specifically, this study involves the application of the NO releasing S-Nitrosothiol, S-Nitrosoglutathione (GSNO) in two variations to determine efficacy against pediatric neuroblastomas and adult breast cancers. Initially, two studies explore the application of GSNO in solution to multiple neuroblastoma cell lines of various origins to determine the potential of NO to act as an adjuvant therapeutic in the clinical management of the prevalent pediatric cancer neuroblastoma. These studies highlight the incredible impact of NO on clonogenic capacity as well as remarkable discriminatory characteristics between neoplastic and healthy cells. Further, the insight presented regarding the mechanism of action of NO on neuroblastomas expands the comprehension of NO-based anticancer therapeutics. Excitingly, when the same GSNO preparation is subsequently applied to more common adult breast cancers to determine if therapeutic efficacy is maintained, results display analogous consequences to those mentioned above. The final study in this dissertation will also explore another application of solution-phase GSNO to adult breast malignancies by combining it with a novel SMYD-3 inhibitor, termed Inhibitor-4 (by collaborators). Since Inhibitor-4 has been shown to similarly impact viability, clonogenic capacity, and apoptosis, this combination is expected to reveal a greater impact than each individual treatment. Overall, an analysis of the significance and feasibility of NO-based therapeutics, delivered via GSNO, is explored to determine their potential application in the clinical management of various cancers. Ultimately, this work expands the knowledge of the practicality, mechanism of action, and effectiveness of NO-based anticancer therapeutics in various cancers with a specific focus on its applicability in neuroblastomas, a malignancy where minimal focus has been placed on NO as a treatment option.
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Subject
cancer
nitric oxide
therapeutic
neuroblastoma
breast cancer
pediatric