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3D Bioprinted Multidrug Resistance (MDR)-Dependent Tumor Spheroids
Minki Hong1, Sera Hong1, Joon Myong Song1
1College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
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.
Insights
This study developed a 3D bioprinting platform to assess cancer drug resistance. The platform accurately predicts chemotherapy effectiveness by considering multidrug resistance (MDR) phenotypes in tumor spheroids.
Area of Science:
- Biotechnology
- Cancer Research
- Pharmacology
Background:
- Multidrug resistance (MDR) in cancer cells is a major challenge in chemotherapy, driven by ATP-binding cassette (ABC) transporters.
- Accurate drug screening requires consideration of varying MDR levels in different cancer types.
- Tailoring chemotherapy dosage based on individual MDR profiles is crucial for treatment efficacy.
Purpose of the Study:
- To establish a 3D bioprinting-based platform for evaluating anticancer drug efficacy.
- To investigate the correlation between MDR phenotypes and drug response in tumor spheroids.
- To demonstrate the utility of this platform in drug discovery and personalized medicine.
Main Methods:
- Fabrication of three-dimensional (3D) tumor spheroids from HeLa, HepG2, and A549 cells using 3D bioprinting.
- Characterization of MDR phenotypes (MRP1 and BCRP expression) in the fabricated spheroids.
- Quantitative assessment of doxorubicin (DOX) efficacy using EC50 values against 2D cells and 3D spheroids, with and without ABC transporter inhibitors.
Main Results:
- 3D bioprinted tumor spheroids successfully retained their native MDR phenotypes.
- Doxorubicin (DOX) showed significantly higher EC50 values (over 2-fold) in 3D spheroids compared to 2D cells.
- DOX efficacy in spheroids was proportional to ABC transporter expression levels, with A549 spheroids exhibiting the highest resistance.
- ABC transporter inhibitors (MK-571 and NOV) significantly reduced DOX EC50 values in resistant spheroids.
Conclusions:
- The 3D bioprinting platform effectively models cancer MDR phenotypes.
- This platform enables quantitative evaluation of anticancer drug efficacy, accounting for MDR.
- The findings support the development of personalized chemotherapy strategies and improved drug screening processes.
