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Document Type

Thesis - University Access Only

Award Date

2015

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Xiangming Guan

Abstract

Cancer metastasis is the major cause of cancer mortality. Despite extensive research efforts, effective treatment and/or prevention for cancer metastasis is still lacking. Cancer metastasis involves cancer cell detachment, migration, invasion, and adhesion at a site different from the original tumor. Cancer cell detachment is the first and required step for metastasis. Glutathione disulfide (GSSG) is the oxidized form of glutathione (GSH). GSH is present in the biological system in millimolar concentration, and is the major antioxidant in the system. GSSG is an indicator of cellular oxidative stress. The impact of GSSG on cellular functions has not been fully explored due to the fact that GSSG is not cell membrane permeable and a lack of method to specifically increase GSSG in cells. We have developed GSSG liposomes that effectively deliver GSSG to cells. Interestingly, cells treated with GSSG liposomes for 24 hours were resistant to detachment by trypsinization. This observation led to this investigation to explore the anti-metastatic effect of GSSG liposomes. Our data demonstrates that GSSG liposomes at 1 mg/mL completely blocked cell detachment and migration in all tested cell lines. The invasion inhibition experiment revealed that GSSG liposomes produced significant invasion inhibition (80%) for all the tested cell lines that include three human cancer cell lines (NCI-H226, non-small lung cancer; PC-3, prostate cancer; HCT 116, colon cancer) and one murine melanoma cancer cell line (B16-F10). Aqueous GSSG showed no such effect confirming that the effects on cell detachment, migration, and invasion were caused by the intracellular delivery of GSSG. There was no difference in cell viability between cells treated with GSSG liposomes and control (untreated) cells. Finally, the in vivo anti-metastatic effect of GSSG liposomes was investigated in a murine melanoma metastasis model. Our data also demonstrated that GSSG liposomes completely prevented melanoma lung metastasis. Further investigation revealed that GSSG liposomes effectively caused a cytostatic effect on melanoma and lung cancer cells, while exhibiting no caspase-3 mediated apoptosis. Our data also showed that GSSG liposomes exhibited no effect on cell cycle distribution in both the cell lines tested (NCI-H226 lung cancer cells, B16-F10 melanoma cells). GSSG liposome treatment of female C57BL mice implanted with B16-F10 cells significantly inhibited tumor growth and also increased mouse survival rates. Finally, preliminary in vivo toxicity studies revealed that GSSG liposomes exhibit no toxicity at a dosage 6 times of the effective dosage. In conclusion, our data confirm that GSSG liposomes exhibit impressive antimetastatic and anti-tumor progression effects both in vitro and in vivo.

Library of Congress Subject Headings

Cancer invasiveness Antioxidants Metastasis Glutathione Liposomes

Description

Includes bibliographical references

Format

application/pdf

Number of Pages

101

Publisher

South Dakota State University

Rights

In Copyright - Educational Use Permitted
http://rightsstatements.org/vocab/InC-EDU/1.0/

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