Author

Jake Tyler

Date of Award

Spring 2020

Document Type

Open Access Thesis

Department

Biological Sciences

First Advisor

Hexin Chen

Abstract

According to breast cancer statistics, 279,100 new cases are expected in the United States in 2020 (Siegel et al., 2020). Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a significantly shorter median overall survival compared to other subtypes of breast cancer. Unlike hormone-positive or HER2-positve breast cancers with effective hormonal or targeted therapies available, there has been very little clinical success from targeted therapies for TNBC. Doxorubicin (Dox) is one of the most used chemotherapy drugs. The only limitation of Dox treatment is its cytotoxicity. Berbamine dihydrochloride (BBM) is a natural benzylisoquinoline alkaloid that is extracted from the plant, Berbaris amurensis. It has been used in Ayurvedic and Chinese medicine to treat clinical patients with inflammation and cancer for many years. In order to improve the efficacy of Dox and reduce its toxicity, we screened a natural product called BBM that can synergistically inhibit cancer cell growth with Dox in TNBC. This study’s aim was to explore the therapeutic potential of the synergism of Dox with BBM. In this study, we identified that BBM has a synergistic effect with Dox and it increases Dox effectiveness by significantly decreasing the IC50 values of Dox in TNBC. We determined that BBM, an autophagy inhibitor, switches the death mode of Dox from autophagy to apoptosis. We also determined that BBM increases the extracellular ATP secretion and has the potential to trigger immunogenic cell death. These data strongly advocate for the therapeutic potential of the efficacy of Dox with BBM in triple negative breast cancer.

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