# Molecular Strategies to Examine and Exploit the Role of Iron in Cell Proliferation and Malignancy

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $285,393

## Abstract

PROJECT SUMMARY
Iron plays a central role in cell proliferation and has been implicated in several aspects of cancer biology.
Malignant cells harbor an altered iron metabolism aimed at increasing iron acquisition and retention, thereby
supporting rapid proliferation rates. Iron scavengers, including several clinical chelators for the treatment of
iron overload, exhibit antiproliferative properties, albeit in the presence of narrow therapeutic windows and
systemic toxicity in several cases. The higher demand for iron of cancer cells is now recognized as an
important area of investigation and a therapeutic opportunity; however, currently available chelator systems are
not designed specifically to target intracellular iron in malignant cells. This research program seeks to engineer
contemporary approaches to iron chelation, particularly to improve our control of intracellular delivery and
tumor selectivity as well as our understanding of the parameters correlated to iron deprivation in cell
proliferation and malignancy. Under the first specific aim of the project, we build on our work on prochelator
systems that are activated for iron coordination upon cell entry. Parameters affecting intracellular oxidative
reactivity and toxicity will be assessed and tuned in several tridentate scaffolds. Within the second aim, tumor-
targeting units are connected to prochelators designed to increase cancer selectivity. The study of a new class
of glycoconjugate constructs takes advantage of the glucose avidity of malignant cells. In addition, the
reactivity of acquired cysteine residues in oncogenic mutant proteins will be employed to activate prochelators
in cancer cells carrying a specific mutation. Under the third aim of the project, the effects of the chelator
systems on the cytosolic labile iron pool will be assessed through several spectroscopic methods. Their impact
on iron homeostasis will be examined through the post-transcriptional regulation and expression of proteins
involved in iron uptake, transport, and storage. Finally, our analyses of cell cycle, death and metabolic
parameters will contribute to delineate the effective cellular susceptibility to our chelator systems. Breast,
colon, and pancreatic cancer cell lines were selected for this study because the implication of iron in their
progression and aggressive phenotypes is documented in cell studies, animal models, and clinical data. This
study is innovative in its combination of principles of iron coordination chemistry with pro-drug and tumor-
targeting approaches for intracellular iron binding. Motivated by the increased iron needs of all cancer
phenotypes, this research program is poised to produce broadly applicable iron-binding strategies and
fundamental information on their impact in cell cycle progression with the long-term goal of identifying new
potential avenues for cancer treatment.

## Key facts

- **NIH application ID:** 9999008
- **Project number:** 5R01GM127646-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Elisa Tomat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $285,393
- **Award type:** 5
- **Project period:** 2018-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999008

## Citation

> US National Institutes of Health, RePORTER application 9999008, Molecular Strategies to Examine and Exploit the Role of Iron in Cell Proliferation and Malignancy (5R01GM127646-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999008. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*