Title

The Potential of Ruthenium-substituted, NGR-tagged Rubredoxin to Act as a Cancer Therapeutic Drug

Date of Award

7-2019

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Francis E Jenney, Jr, PhD

Second Advisor

Kimberly Baker, PhD

Third Advisor

Abigail Hielscher, PhD

Fourth Advisor

Richard White, PhD

Abstract

Most cancer treatments have unwanted side effects due to the lack of selectivity of the treatment. Pyrococcus furiosus is a hyperthermophile that grows optimally at extreme temperatures. A protein of particular interest produced by P. furiosus is called rubredoxin (PfRd). PfRd is a highly stable, non-heme, iron-containing protein. The iron core is held in place by four cysteinyl sulfur ligands. PfRd has unique properties that make the protein a potentially valuable medical tool, including stability under extreme conditions. Previous work has shown ruthenium-substituted, NGR-tagged rubredoxin (RuRd-NGR) binds to the Aminopeptidase-N/CD13 (APN/CD13) receptor on human fibrosarcoma (HT- 1080) cells. Once bound, apoptosis is induced, ultimately killing the cells. The purpose of the project is to examine RuRd-NGR as a potential selective cancer therapeutic drug. E. coli cells were transformed with a plasmid that allowed for the expression of NGR-tagged rubredoxin. Following expression, NGR-tagged rubredoxin was purified and the native iron atom was substituted with a ruthenium atom, a known cytotoxic metal. The NGR tumor-homing peptide conferred binding specificity to the APN/CD13 receptor on HT-1080 cells, as shown via a binding assay and binding competition assay. Additionally, the RuRd-NGR treatment group caused significant cell death in the HT-1080 cell line (p

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