Affiliation:
1. Leiden University Medical Center
Abstract
Abstract
Tissue-specific drug uptake has not been well studied, compared to the deeper understanding of drug resistance mediated by the cellular efflux system such as MDR1 proteins. It has been suggested that many drugs need active or defined transporters to pass the cell membrane. In contrast to efflux components that are induced after anti-cancer drugs reach the intracellular compartment, drug importers are required for initial drug responses. Furthermore, tissue-specific uptake of anti-cancer drugs may directly impact the side effects of many drugs when they accumulate in healthy tissues. Therefore, linking anti-cancer drugs to their respective drug import transporters would directly help to predict drug responses, whilst minimizing side effects. We designed and applied customized CRISPR activation and knockout libraries targeting all potential human transporters to identify potential drug transporters of the commonly used anti-cancer drug doxorubicin. Integrating the data from these comprehensive CRISPR screenings, we confirmed previously indicated doxorubicin exporters such as ABCB1 and ABCG2 genes, and identified novel doxorubicin importer gene SLC2A3 (GLUT3). The newly identified importers may have direct clinical implications for the personalized application of doxorubicin in treating distinct tumors.
Publisher
Research Square Platform LLC
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