期刊
SCIENTIFIC REPORTS
卷 11, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41598-021-89931-9
关键词
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资金
- Indo-Australia Science and Technology Fund [ST040007]
- Victorian Cancer Agency Platform Technology Capacity Building Grant [PTCP-02]
- CASS Foundation (Australia)
Inhibiting MDR1 or ABCG2 was found to increase the sensitivity of liver cancer stem cells to doxorubicin, leading to elevated intracellular concentration of the drug and increased apoptosis. This approach effectively reversed chemoresistance in liver cancer stem cells, demonstrating a promising strategy for enhancing the therapeutic efficacy of doxorubicin.
Two ATP-binding cassette transporters, ABCB1/MDR1 and ABCG2/BCRP, are considered the most critical determinants for chemoresistance in hepatocellular carcinoma. However, their roles in the chemoresistance in liver cancer stem cells remain elusive. Here we explored the role of inhibition of MDR1 or ABCG2 in sensitizing liver cancer stem cells to doxorubicin, the most frequently used chemotherapeutic agent in treating liver cancer. We show that the inhibition of MDR1 or ABCG2 in Huh7 and PLC/PRF/5 cells using either pharmacological inhibitors or RNAi resulted in the elevated level of intracellular concentration of doxorubicin and the accompanied increased apoptosis as determined by confocal microscopy, high-performance liquid chromatography, flow cytometry, and annexin V assay. Notably, the inhibition of MDR1 or ABCG2 led to the reversal of the chemoresistance, as evident from the enhanced death of the chemoresistant liver cancer stem cells in tumorsphere-forming assays. Thus, the elevation of effective intracellular concentration of doxorubicin via the inhibition of MDR1 or ABCG2 represents a promising future strategy that transforms doxorubicin from a traditional chemotherapy agent into a robust killer of liver cancer stem cells for patients undergoing transarterial chemoembolization.
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