3D Bioprinted Multidrug Resistance (MDR)-Dependent Tumor Spheroids

Abstract

Multidrug resistance (MDR) refers to the ability of cancer cells to resist various anticancer drugs and release them from the cells. This phenomenon is widely recognized as a significant barrier that must be overcome in chemotherapy. MDR varies depending on the number and expression level of the ATP-binding cassette transporter (ABC transporter), which is expressed differently in various cancer cells. Therefore, the dose of anticancer drugs should be adjusted according to the extent of MDR. The demand for drug screening that considers the differences in MDR is increasing in the process of drug discovery. In this study, three types of tumor spheroids were fabricated from HeLa (MRP1^–/BCRP^–), HepG2 (MRP1⁺/BCRP^–), and A549 cells (MRP1⁺/BCRP⁺) using three-dimensional (3D) bioprinting. The fabricated tumor spheroids maintained their own MDR phenotypes. The EC₅₀ values of doxorubicin (DOX) against the three tumor spheroids were more than 2-fold higher than those against the 2D cells. In addition, the EC₅₀ value of DOX against tumor spheroids was proportional to the number of ABC transporters. The EC₅₀ value of DOX against A549 tumor spheroids had the largest value of 9.5 μM among the three spheroids. In addition, the EC₅₀ values of DOX against HepG2 and A549 tumor spheroids were remarkably reduced when they were treated with ABC transporter inhibitors, such as MK-571 against MRP1 and/or NOV against BCRP. These results demonstrate the successful construction of a 3D bioprinting-based screening platform to quantitatively evaluate the anticancer efficacy of chemodrugs, considering the MDR of cancer cells.