Abstract

Multi-drug resistance (MDR) occurs when cancer cells become resistant to multiple chemotherapeutic drugs that are functionally and structurally different. MDR typically leads to chemotherapy treatment failure and, subsequently, poor patient prognosis. Cancers can become resistant to antineoplastic drugs by overexpressing one or more ATP-binding cassette (ABC) transporters that act as drug efflux pumps and expel xenobiotics from cells. One such protein is the Breast Cancer Resistance Protein (BCRP, or ABCG2), which is believed to confer MDR to several types of cancer. Inhibition of BCRP cellular activity is therefore thought as a way to restore sensitivity of MDR cancers to chemotherapeutics.

In previous work, several potential inhibitors of ABC transporters were identified using high-throughput in silico screens (Brewer et al., 2014). Using cell viability and cellular accumulation assays of BCRP substrates, we assessed these compounds for toxicity to cells and the ability to reverse MDR in the BCRP overexpressing breast cancer cell line, MCF7-M100 (Nanayakkara, 2019). Here, cell culture studies of the potential BCRP inhibitors are expanded to two other cell lines, the BCRP overexpressing colon cancer and BCRP overexpressing non-small cell lung cancer cell lines, S1M1-80 and MX20, respectively. For each cell line, the level of BCRP overexpression was assessed at RNA and protein levels and the MDR phenotype was confirmed using cell viability assays. Ability of the compounds to reverse MDR was assessed, as well as the compounds’ toxicity to the cancer cells. Though differences in cell lines were observed, including passage number effects between low and high passage MCF7-M100 cells, three compounds seem to be promising candidates as BCRP mediated MDR reversal agents.

Also presented here is work involving another medically relevant ABC transporter, P-glycoprotein (P-gp, or ABCB1), which, in addition to its role in MDR cancers, is also expressed at the blood-brain barrier (BBB). The BBB protects the brain from xenobiotics and toxins; one way this is accomplished is by the expression of ABC transporters on the luminal side of the BBB which expel toxins from the brain. This expelling action becomes an issue with drug delivery to the brain when treating diseases such as epilepsy and brain cancers. A group of compounds were tested in the brain capillary endothelial cell line hCMEC/d3 for their ability to modulate the action of P-gp at the BBB. These compounds seem to be promising candidates for further research into inhibiting ABC transporters at the blood-brain barrier.

Degree Date

Spring 5-16-2020

Document Type

Thesis

Degree Name

M.S.

Department

Biological Sciences

Advisor

Dr. Pia Vogel

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

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