Dissertation
Enhancing non-small cell lung cancer therapy with superoxide dismutase mimetics and pharmacological ascorbate
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2024
DOI: 10.25820/etd.007644
Abstract
Lung cancer is the leading cause of cancer associated mortality and non-small cell lung cancer (NSCLC) comprises roughly 80% of these cases. Currently, NSCLC therapy involves a combination of radiation and platinum-based chemotherapy. While these treatment modalities have proven effective, they are also associated with normal tissue toxicity impacting quality of life in these patients. This thesis studies redox active small molecules as adjuvants in NSCLC cancer therapy that both: 1) protect normal tissue from toxicity related to radio-chemotherapy by acting as an antioxidant; and 2) act in a pro-oxidant fashion in cancer cells to improve the tumor therapeutic efficacy based on fundamental differences in cancer and normal cell metabolism.
Cisplatin, the most utilized chemotherapy in NSCLC therapy, contributes to the development of acute kidney injury (AKI) and chronic kidney disease (CKD), with a more pronounced effect in elderly patients. We hypothesized that small molecule penta-aza-macrocyclic Mn (II)-containing (MnPAM) superoxide dismutase mimetic Avasopasem manganese (AVA) would be protective in rodent models of AKI and CKD. Young and old C57Bl/6J murine models of cisplatin induced AKI and CKD were treated with AVA to investigate potential antioxidant and anti-inflammatory effects. Cisplatin-induced AKI and CKD were found in both young and old mice, though more pronounced in older mice as determined by increased mortality, serum creatinine, serum blood urea nitrogen, kidney expression of damage markers KIM-1 and NGAL, and histological assessment. In addition, AVA treatment was associated with reduction in inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1, in AVA treated kidneys. AVA also alleviated cisplatin-induced alterations in kidney mitochondrial electron transport chain (ETC) complex activity and NADPH oxidase 4 (NOX4) expression. These results support the hypothesis that older mice are more susceptible to cisplatin-induced AKI and CKD and AVA supplementation alleviates cisplatin-induced AKI and CKD.
To further support the use of MnPAM dismutase mimetics in NSCLC therapy, murine models of cardiac targeted irradiation (CTI), showed that MnPAM dismutase mimetic, Rucosopasem manganese (RUC), is protective in cardiac targeted radiation. C57Bl/6J mice were exposed to 16 gray (Gy) cardiac radiation (~30 min before radiation), and subsequently for 5 days following radiation followed by weekly dosing to 9 months. RUC treated animals demonstrated increased survival and preservation of diastolic and systolic output as well as overall cardiac output. Further, RUC was shown to reduce expression of fibrosis makers transforming growth factor beta (TGFβ) and connective tissue growth factor (CTGF) in heart homogenate 9 months post radiation. This data supports the hypothesis that RUC enhances protection of cardiac tissue exposed to radiation.
In addition, MnPAM dismutase mimetics and Pharmacological ascorbate (P-AscH‾, IV ascorbate to achieve [mM] plasma levels) have been shown to act individually as cancer cell radiosensitizers via the generation of H2O2 in vivo. The current study shows that the combination of RUC, with P-AscH‾ radio-sensitizes NSCLC and increases steady state levels of intracellular H2O2 with no additional toxicity to normal human bronchial epithelial cells (HBECs). Conditional over expression of catalase (CAT) in H1299T CATc15 cells demonstrated that the combination of RUC and P-AscH‾ caused radio-sensitization through an H2O2-dependent mechanism. Interestingly, RUC combined with P-AscH‾ demonstrated more than additive cytotoxicity in both H1299T and A549 NSCLC cells, but conditional over expression of ferritin heavy chain (FtH) only protected the H1299T, and not the A549, from this toxicity. Most importantly, the combination of RUC + P-AscH‾ was found to sensitize to radio-chemotherapy with cisplatin (CIS) + etoposide (ETOP) in both H1299T and A549 cell types. Finally, in H1299T NSCLC xenografts the combination of RUC + P-AscH‾ with cisplatin and etoposide + radiotherapy (24 Gy radiation (12 x 2 Gy fractions)) significantly inhibited tumor growth and increased median overall over survival.
Overall, the results of this work support the hypothesis that MnPAM dismutase mimetics + P-AscH‾ enhance the efficacy of radio-chemotherapy in NSCLC through a mechanism governed by redox active metals and H2O2 production. Furthermore, this approach may also protect normal tissue from radio-chemotherapy, opening a therapeutic window for increasing treatment outcomes in NSCLC .
Details
- Title: Subtitle
- Enhancing non-small cell lung cancer therapy with superoxide dismutase mimetics and pharmacological ascorbate
- Creators
- Casey F. Pulliam
- Contributors
- Douglas R. Spitz (Advisor)Bryan G. Allen (Committee Member)Garry R. Buettner (Committee Member)Mitchell C. Coleman (Committee Member)Joseph J. Cullen (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Human Toxicology
- Date degree season
- Autumn 2024
- DOI
- 10.25820/etd.007644
- Publisher
- University of Iowa
- Number of pages
- xvi, 178 pages
- Copyright
- Copyright 2024 Casey F. Pulliam
- Language
- English
- Date submitted
- 12/06/2024
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 119-172).
- Public Abstract (ETD)
Lung cancer is the leading cause of cancer related deaths. Research in treatment has led to developments in chemotherapy and radiation, often increasing survival times for patients and sometimes even cures. However, these advancements come with drawbacks as the very tools of treatment can cause damage to non-cancer tissue, leading to reduced quality of life in patients following therapy. Therefore, efforts to improve therapy going forward must focus not only on further improving current therapies, but also protecting normal tissue. To this end, we have employed small molecules that take advantage of fundamental differences between cancer and normal cell oxidative metabolism.
Superoxide dismutase (SOD) mimetics and pharmacological ascorbate (P-AscH‾) are examples of redox active agents. These drugs have been found to not only increase the efficacy of traditional therapy, but also protect normal tissue, through similar mechanisms. This work demonstrates that selective superoxide dismutase mimetics exhibit remarkable protective effects against the toxicity of cisplatin, a common chemotherapeutic agent used in lung cancer therapy, in kidneys of older rodents in two models of cisplatin induced kidney disease. We further show that SOD mimetics are protective against toxicity induced by radiation that is targeted to the heart. Finally, we demonstrate the by combining SOD mimetics and P-AscH‾, we can improve the effects of radiation and chemotherapy on lung cancer cells themselves, in both in vitro and in rodent models. This work provides evidence that redox based drugs, namely SOD mimetics and P-AscH‾, could be powerful tools in the treatment of lung cancer.
- Academic Unit
- Interdisciplinary Studies Program
- Record Identifier
- 9984774959702771
Metrics
1 File views/ downloads
31 Record Views