In vitro Reversal of Multidrug Resistance in Cancer

Abstract

Multi‐drug resistance (MDR) occurs when cancer cells become resistant to multiple chemotherapeutic drugs that are functionally and structurally different. MDR usually leads to failure of chemotherapy treatment and subsequently to poor patient prognosis. Cancers can become resistant to antineoplastic drugs by over‐expressing 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 to chemotherapeutics. In previous work, we identified several potential inhibitors of BCRP using high‐throughput in silico screens. 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. Here we expand our studies of the potential BCRP inhibitors to two other BCRP‐overexpressing cell lines, the BCRP overexpressing colon cancer and 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 level and the MDR phenotype was confirmed using cell viability assays. The effects of our newly discovered inhibitors on reversing MDR in these two cell lines is reported.Support or Funding InformationThis work is supported by the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, and private gifts from Ms. Suzy Ruff of Dallas, Texas, and Ms. Myra Williams, Ph.D., of Naples, FL.