Subject Area

Biochemistry, Biological Sciences, General, Cell Biology, Molecular Biology

Abstract

One of the major causes of treatment failure in aggressive cancers is multidrug resistance (MDR), which is linked to the overexpression of membrane efflux proteins that export chemotherapeutics from cancer cells. This mechanism prevents chemotherapeutic drugs from reaching cytotoxic concentrations intracellularly, allowing the cancer to survive. Two primary mediators of this mechanism are P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). P-gp and BCRP are transmembrane ATP-binding cassette (ABC) transporters that are frequently overexpressed in MDR cancers. They utilize the binding and hydrolysis of ATP to transport a diverse range of amphipathic molecules of varying size (Schinkel and Jonker, 2003), and this broad substrate spectrum enables them to efflux cytotoxic compounds from cells throughout the body. Consequently, P-gp and BCRP are associated with MDR to chemotherapy across many cancer types (Lee et al., 2010). Despite over 40 years of intensive research, no clinically applicable inhibitors have been identified, and MDR remains an important unmet need in oncology.

Computational methods have been employed previously by our group to identify drug-like compounds that, when co-administered with chemotherapeutics, restore cancer cell sensitivity to treatment. Several novel compounds were identified that inhibit the biochemical function of P-gp (Brewer et al., 2014), validating the computational approach. Subsequent studies demonstrated that these compounds re-sensitized multidrug resistant prostate cancer cells in culture to chemotherapeutics, nearly to the level of non-resistant parental cells (Follit et al., 2015), qualifying them as leads for future drug development. This approach was novel because the inhibitors were targeted towards the energy-harvesting parts of the enzyme and not the drug transporting domains.

Improved computational methods have since identified additional compounds that were capable of reversing P-gp-mediated MDR in prostate cancer cells (McCormick et al., 2025). Nine compounds were found to also reverse MDR in the aggressive ovarian cancer cell line A2780ADR in culture (Follit et al., 2015). The in vitro application of these novel compounds provides a platform to assess whether reduced chemotherapeutic dosing can still achieve therapeutic success, potentially improving quality of life for patients undergoing chemotherapy and lessening potential side effects.

Degree Date

Spring 5-16-2026

Document Type

Thesis

Degree Name

M.S.

Department

Biological Sciences

Advisor

Pia Vogel

Number of Pages

72

Format

.pdf

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

Download

Share

COinS