Doctoral Dissertations

Orcid ID

0000-0002-0173-7763

Date of Award

8-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Hwa-Chain Robert Wang

Committee Members

Steven A. Ripp, Qixin Zhong, Timothy E. Sparer

Abstract

Cancer is a deadly malignant disease that is costly to treat and still impossible to cure. Cancer treatments often come with side effects that impact the overall health of patients. Breast cancer is the most common type of cancer in the United State and bladder cancer mortality and recurrence rates are still high among cancer patients. Thus, safe and effective regimens are needed to combat these diseases.

In this study, the safe and efficacious combination of gemcitabine, cisplatin, and romidepsin (Gem plus Rom+Cis) to treat two types of cancer: bladder and breast cancer, was formulated. In vitro data from this study revealed that the combination of Gem plus Rom+Cis synergistically reduced cell vitality, clonogenic survival, invasion, and anchorage independent growth of bladder and breast cancer cell lines. The tolerable drug doses and administration schedules of Gem plus Rom+Cis for mice model were determined. Athymic nude mice (nu/nu) treated with the triple combination showed no significant weight loss or sign of toxicity at the end of studies. Gem plus Rom+Cis efficaciously controls the development of tumors in CDX models. Results showed that breast and bladder CDXs treated with Gem plus Rom+Cis had significantly smaller tumor sizes comparing to double combination of Gem plus Cis or Rom+Cis or untreated control. Data from urothelial carcinoma studies revealed that the apoptosis of bladder cancer cells was found to be enhanced through the ERK-Nox-1 pathway via reactive oxygen species (ROS) induction. Furthermore, drug resistance was reduced due to the suppression of glutathione (GSH) and possibly by reducing factors that associated with epithelial to mesenchymal transition (EMT). The data also suggested that the combination reduced invasiveness and anchorage independence in cancer cell lines as a consequence of suppressing the expression levels of proteins that are related to metastasis and EMT process.

In conclusion, this triple combination was revealed to be more effective in controlling tumor development than double or mono anti-cancer therapy. Thus this combination should be considered as an advanced regimen for cancer treatment that hopefully could be translated into a clinical trial to reduce cancer-related mortality and improved quality of life for cancer patients.

Comments

Parts of this dissertation were slightly modified version of articles that has been accepted for publication in Cancer Chemotherapy and Pharmacology and British journal of Cancer

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