1 research outputs found
Overcoming Multidrug Resistance by Base-Editing-Induced Codon Mutation
Multidrug
resistance (MDR) is the main obstacle in cancer chemotherapy.
ATP binding cassette (ABC) transporters on the MDR cell membrane can
transport a wide range of antitumor drugs out of cells, which is one
of the main causes of MDR. Therefore, disturbing ABC transporters
becomes the key to reversing MDR. In this study, we implement a cytosine
base editor (CBE) system to knock out the gene encoding ABC transporters
by base editing. When the CBE system works in MDR cells, the MDR cells
are manipulated, and the genes encoding ABC transporters can be inactivated
by precisely changing single in-frame nucleotides to induce stop (iSTOP)
codons. In this way, the expression of ABC efflux transporters is
reduced and intracellular drug retention is significantly increased
in MDR cells. Ultimately, the drug shows considerable cytotoxicity
to the MDR cancer cells. Moreover, the substantial downregulation
of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)
implies the successful application of the CBE system in the knockout
of different ABC efflux transporters. The recovery of chemosensitivity
of MDR cancer cells to the chemotherapeutic drugs revealed that the
system has a satisfactory universality and applicability. We believe
that the CBE system will provide valuable clues for the use of CRISPR
technology to defeat the MDR of cancer cells