Leveraging iron dysregulation for improved therapeutic outcomes in non-small cell lung cancer

Lung cancer is the leading cause of cancer-related deaths in the United States, with non-small cell lung cancer (NSCLC) accounting for 84% of cases. Despite advances in treatment, only 26% of people diagnosed with NSCLC survive five years after diagnosis, highlighting the need for novel therapies. Cancer cells have higher levels of reactive oxygen species such as hydrogen peroxide (H₂O₂) and a greater accumulation of iron (Fe²⁺). H₂O₂ and Fe²⁺ can react to cause damage to proteins and DNA. This thesis explores development of therapies that increase or decrease Fe²⁺ to enhance cancer cell death in NSCLC. The first part of the research explored whether decreasing Fe²⁺ using genetic and pharmacological tools in lung cancer cells can enhance cancer cell death by making them more sensitive to current treatments like chemotherapy and radiation. Results from this study demonstrated that decreasing Fe²⁺, made lung cancer cells more likely to be damaged due to genomic instability, more sensitive to chemotherapy and radiation and thus enhanced cancer cell death. The second part of the research investigated whether increasing Fe²⁺ using iron-oxide nanoparticles (tiny particles used to treat iron deficiency) can boost the effectiveness of a high-dose vitamin-C treatment in lung cancer cells. Combining these two treatments led to increased Fe²⁺ and enhanced lung cancer cell death through an H₂O₂-mediated DNA damage mechanism. In summary, this research demonstrated that manipulating iron levels in cancer cells can enhance the effectiveness of current treatments, potentially improving survival rates for lung cancer patients.