Spheroids as 3D Cell Models for Testing of Drugs

Cell lines are an important tool for scientific research and clinical and pharmaceutical applications. Cells are isolated from animal tissues and can be expanded in culture to study cell biology and disease. The isolated cells can be used to produce antibodies, proteins, and vaccines. Immortalized cell lines can grow in vitro and are commonly used as models for complex biology. The most frequently used type of cell culture for scientific research and clinical and pharmaceutical applications is the two-dimensional (2D) model, but recently, the popularity of the three-dimensional (3D) cultivation method is growing

Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance

Multidrug resistance (MDR) is a common problem when fighting cancer with chemotherapy. P-glycoprotein (P-gp, or MDR1) is an active pump responsible for the efflux of xenobiotics out of the cell, including anti-cancer drugs. It is a validated target against MDR. No crystal structure of the human P-gp is available to date, and only recently several cryo-EM structures have been solved. In this paper, we present a comprehensive computational approach that includes constructing the full-length three-dimensional structure of the human P-gp and its refinement using molecular dynamics. We assessed its flexibility and conformational diversity, compiling a dynamical ensemble that was used to dock a set of lignan compounds, previously reported as active P-gp inhibitors, and disclose their binding modes. Based on the statistical analysis of the docking results, we selected a system for performing the structure-based virtual screening of new potential P-gp inhibitors. We tested the method on a library of 87 natural flavonoids described in the literature, and 10 of those were experimentally assayed. The results reproduced the theoretical predictions only partially due to various possible factors. However, at least two of the predicted natural flavonoids were demonstrated to be effective P-gp inhibitors. They were able to increase the accumulation of doxorubicin inside the human promyelocytic leukemia HL60/MDR cells overexpressing P-gp and potentiate the antiproliferative activity of this anti-cancer drug