Inhibition of BCRP in Multidrug Resistant Cancer using Novel Inhibitors

Abstract

Multi‐drug resistance (MDR) occurs when cancer cells become resistant to a diverse array of chemotherapeutics and xenobiotics. Among the many mechanisms of MDR, one of the most prominent is the overexpression of ATP‐binding cassette (ABC) transporters. ABC transporters harness the energy from ATP hydrolysis to transport xenobiotics, drugs, and other toxic compounds out of the cell. When ABC transporters are overexpressed in cancer cells, their efflux activity can lower the intracellular concentration of medicinal compounds to sub‐therapeutic levels. One member of the ABC transporter family, the Breast Cancer Resistance Protein (BCRP, or ABCG2), confers MDR to a variety of cancers. Transient inhibition of BCRP should therefore restore sensitivity of resistant cells to chemotherapeutics. In previous work by our lab, several potential BCRP inhibitors were identified via computational methods. Using cell viability assays, we tested the potential BCRP inhibitors using a BCRP overexpressing cell line. Here we compare the effectiveness of the inhibitors at re‐sensitizing the cells to Mitoxantrone relative to the parental cell line which does not overexpress BCRP. The potential toxicities of the experimental compounds were also assessed using the non‐cancerous HFL1 cell line.

Gene therapy: A promising approach for breast cancer treatment

“…Multiple drug resistance (MDR) is caused by the high expression of MDR transporters such as P‐glycoprotein (P‐gp/ABCB1), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance protein‐1 (MRP1/ABCC1) 37 . These transporters can be in the plasma membrane of the cell or in the nuclear membrane, causing inadequate drug concentrations in the target cell and ultimately reducing toxicity in the cancer cell 38 . P‐gp is encoded by MDR1 gene and is a 170 kDa plasma membrane protein.…”