Subject Area
Cell Biology, Molecular Biology, Life Sciences, Pharmacology
Abstract
Chemotherapy is one of the most effective methods for treating metastatic cancers. However, when the cancer cells develop tolerance for structurally or functionally different therapeutic agents, so-called multidrug resistance (MDR), it becomes a major obstacle for positive therapeutic outcomes. The major contributing factor for MDR is the overexpression of efflux drug transporters which belong to the ATP-binding cassette (ABC) family of proteins that have the ability to affect chemotherapy treatments by lowering the intracellular accumulation of various anti-cancer drugs. Many of the human ABC proteins are efflux transporters and among them, P-glycoprotein (P-gp/ABCB1), the multidrug resistance-associated proteins (MRPs/ABCCs), and the breast cancer resistance protein (BCRP/ABCG2) are mainly involved in causing MDR in cancers.
Both P-gp and BCRP restrict the accumulation of their substrates (chemotherapeutics and other toxins) inside cells. Both of them therefore have protective roles in preventing cells from exposure to potentially harmful substances. They are typically expressed at physiological barriers such as the blood brain barrier, placenta, blood testis barrier and gastrointestinal tract among others.
In cancer cells, BCRP plays a major role in the multi drug resistance by overexpression of the protein, enhanced export of the chemotherapeutic drugs and thereby acquired resistance to various chemotherapeutics, including mitoxantrone, methotrexate, topotecan, doxorubicin, and many others. Extensive efforts have been made to identify small molecules that inhibit BCRP function. To date, however, none of the BCRP inhibitors discovered so far has been successful in clinical settings.
Most of the previously found inhibitors of BCRP are likely bound to the transmembrane, drug-binding domain (DBD) and were likely to be BCRP substrates. In this work we are presenting our efforts to identify specific inhibitors of BCRP that target the nucleotide binding domains of the protein, blocking either the binding or hydrolysis of ATP, which is required for drug export. Such inhibitors might provide novel candidates for future drug development strategies to overcome multidrug resistance in cancers.
Degree Date
12-21-2024
Document Type
Dissertation
Degree Name
Ph.D.
Department
Biological Sciences
Advisor
Pia D. Vogel
Number of Pages
128
Format
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Recommended Citation
Lowe, Jesiska, "Reversing Cancer Multidrug Resistance in vitro" (2024). Biological Sciences Theses and Dissertations. 29.
https://scholar.smu.edu/hum_sci_biologicalsciences_etds/29
