Recent research suggests that copper chelation may be an effective treatment for certain types of lung cancer, particularly in cells that have two notable features: a heightened response of transcription factors to oxidative stress and lower levels of available copper. The connection between copper imbalances and the growth of cancer cells, along with other health issues, has been acknowledged for quite some time.
The Chang Lab at Princeton Chemistry is focused on examining how metal nutrients influence human biology. After studying iron last year, the lab is now concentrating on copper this year. Their first publication of 2025 introduces an innovative sensing probe designed to identify copper in human cells, which the lab uses to investigate the role of copper in the growth of lung cancer cells.
In their latest investigations, researchers suggest a new approach to treatment where copper chelation demonstrates promising outcomes for specific lung cancers that show an increased transcription factor associated with oxidative stress and a reduced availability of copper.
Their collaborative paper, A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer, was published this week in the Proceedings of the National Academy of Sciences. This study follows another published in July 2024 that focused on iron, further solidifying the lab’s proficiency in transition metal signaling.
In their recent experiments, the lab’s innovative histochemical sensing probe was utilized across various human tumor cell lines obtained from the National Cancer Institute to pinpoint cell types with elevated copper levels. While copper is essential for health, its imbalances are frequently linked to cancer cell growth and other health problems. The delicate equilibrium of copper in mammals can be easily disrupted, increasing the demand for tools to investigate and monitor copper-dependent cell growth, a process referred to as cuproplasia.
“Copper is an essential metal nutrient crucial for health. It is derived from our diet, reflecting the interaction between genetic and environmental elements, as every single cell in all organisms requires it,” stated Christopher Chang, the Edward and Virginia Taylor Professor of Bioorganic Chemistry. “To comprehend diseases like cancer, we must investigate the underlying factors that govern a cell’s survival or demise and then find methods to mitigate excessive growth.”
“Our goal is to create more sophisticated biomarkers using this technology. We envisioned a technique applicable to various cell types or tissue samples to isolate different cancer cells and evaluate their dependence on cuproplasia,” he noted.
This research was conducted in partnership with Marco Messina at the University of Delaware and Gina DeNicola from the H. Lee Moffitt Cancer Center and Research Institute in Florida.
Connecting Copper and Antioxidants
The researchers have identified a link between copper and a transcription factor called nuclear factor-erythroid 2-related factor 2 (NRF2). Elevated levels of free radicals in cells instigate what researchers term the antioxidant response, which activates NRF2 to bolster the expression of genes responsible for producing proteins that protect against oxidative damage.
The Chang Lab’s research delves into this area, merging sensing techniques and catalysis to pinpoint regions experiencing these alterations.
“Increased copper levels within cells can induce oxidative stress,” commented Aidan Pezacki, co-lead author and graduate student in the Chang Lab. “As a result, we hypothesize that cancers with a substantial requirement for copper-driven growth tend to exhibit elevated oxidative stress levels. Given NRF2’s important role in regulating oxidative stress, we speculated it might also influence copper levels.”
Research indicates that certain lung cancers often exhibit high NRF2 levels. This allowed the researchers to link increased NRF2 with decreased available copper, making the cells more vulnerable to copper chelation. The chelation therapy effectively limits the availability of critical metal nutrients, subsequently curbing cell proliferation.
“Using these NCI cell lines, we applied a copper chelator and analyzed its effects on cells with both low and high NRF2 levels,” Pezacki elaborated. “Our results showed that cells with heightened NRF2 experienced a greater rate of cell death following copper chelation.”
“We believe NRF2 is effectively sequestering copper, and the chelator diminishes copper levels even further. This combined reduction likely fails to satisfy the nutritional needs of the cells, positioning copper chelation as a potentially valuable therapeutic strategy in cancers where copper is already in limited supply and tightly regulated,” he explained.
Chang underscored that these findings have yet to be applied in human tissue testing.
“This research acts as a proof-of-concept for detecting metal weaknesses in lung cancer. We believe this framework could provide insights not just for cancer but also for a broader understanding of cellular growth mechanisms,” Chang stated. “In essence, all diseases are linked to imbalances in cell growth or death. Our studies aim to clarify this balance and contribute to the broader understanding of how diet, environment, and lifestyle affect health outcomes.”
A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer was authored by Marco Messina, Laura Torrente, Aidan Pezacki, Hanna Humpel, Erin Li, Sophia Miller, Odette Verdejo-Torres, Teresita Padilla-Benavides, Donita Brady, David Killilea, Alison Killilea, Martina Ralle, Nathan Ward, Jun Ohata, Gina DeNicola, and Christopher Chang.
This research was supported by funding from the National Institutes of Health (R01 GM 79465, R01 GM 139245, R01 ES 28096, and R01 NIAMS AR077578), the Florida Department of Health (9BC07), and the Agilent Biodesign Program.
