Title

The Potential for Ruthenium-Substituted Rebredoxin with Attached Tumor-Homing Peptide NGR as a Selective Cancer Therapeutic Drug

Date of Award

2016

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Francis E. Jenney, Jr, PhD

Second Advisor

Shafik Habal, MD

Third Advisor

Abigail Hielscher, PhD

Fourth Advisor

Brian Matayoshi, PhD

Abstract

The difficulty in discerning the exact causes of cancer is reflected in the inability to find a truly selective cancer treatment. Many unpleasant side effects of modern treatments are due to lack of selectivity. The utility of recent, more selective cancer treatments is squandered by their lack of generalizability to diverse cancer phenotypes. Currently, tumor-homing peptides and tumor-penetrating peptides are being studied in an effort to increase the selectivity and delivery of anti-cancer compounds. The non-heme iron-containing redox protein, rubredoxin, from the hyperthermophilic archaeon Pyrococcus furiosus is of particular interest due to its thermostability, ease of modification, solubility, and its lack of immunogenicity. Past research has shown that rubredoxin can be mutated to express a tumor-homing peptide, and that its natural iron center can be substituted with other metals. The present study demonstrates the ability to attach a tumor homing peptide containing the NGR motif to rubredoxin and the selectivity of the NGR peptide-tagged Ru-substituted rubredoxin for the human fibrosarcoma cell line (HT1080). We demonstrate the cytotoxic effects of the peptide-tagged Ru-substituted rubredoxin treatments on the HT1080 cell line where incubation with the treatments caused significant apoptosis compared to untreated controls. The finding that the treatments do not have a significant cytotoxic effect on the non-malignant mammary epithelial cell line, MCF1Oa, corroborates the specificity of the tagged rubredoxin treatments.

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