|M.Sc Student||Tal Kfir|
|Subject||Effect of Metallocorroles on Cancer Development in Diabetics|
|Department||Department of Chemistry||Supervisor||Full Professor Gross Zeev|
|Full Thesis text|
Diabetes, particularly type 2 diabetes (T2D), is a growing epidemic worldwide. T2D is characterized by insulin resistance, reduction in insulin signaling and cellular glucose metabolism, which leads to increased levels of insulin (hyperinsulinemia) and blood glucose levels (hyperglycemia). It has recently been shown that T2D increases also breast cancer risk and mortality in human. Female MKR/ mice is a non -obese mice-based model of T2D, characterized by severe insulin resistance and hyperinsulinemia. Since hyperinsulinemia has been reported to increase the risk of breast cancer recurrence and death, female MKR/ mice serve as a good model for studying the role of hyperinsulinemia in cancer progression. Sulfonated gallium(III) corrole (1-Ga), a water soluble and intensely fluorescent corrole, has been shown to an effective antitumor agent, acting by disrupting mitochondrial potential and inducing cytoskeletal changes in cancer cells. In the presence of serum protein, this compound is able to penetrate the cell membrane, as demonstrated both in vitro and in vivo.
This thesis started by investigating the interactions of 1-Ga with insulin and serum components. The focus was on spectral changes occurring upon incubation of 1-Ga with the bio-molecules, which revealed that it interacts with insulin, but that their association is weak relative to other serum proteins. At the cellular level, 1-Ga strongly reduced cancer cells growth, even under hyperinsulinemia conditions. Sulfonated iron(III) corrole (1-Fe), which is known for its ability to reduce oxidative stress and diabetes complications in rats, had no significant effect on cancer cells growth under the hyperinsulinemia conditions used in this thesis. The effect of 1-Ga on tumor reduction was examined in MKR/ and wild type mice by applying 0.01-1 mg/kg/day (by Intraperitoneal injection) for 7-14 days after measurable tumor size was recognized, in comparison to mice treated with saline. Unfortunately, no significant changes were recorded between the different groups, neither between treated and untreated nor between MKR/ and wild type mice. We assume that the cell line, mice model or the drug provision method are not suitable this kind of experiment, and further research should be done.
In order to study the pharmacokinetics of 1-Ga?, several tests for its extraction out of human serum were investigated. The optimal conditions were to treat corrole-containing serum by 38 % HCl, followed by extracting of 1-Ga into ethyl acetate. This procedure allowed for detection limits in the micro-molar range.