NRF 2/ ABCB 1‐mediated efflux and PARP 1‐mediated dampening of DNA damage contribute to doxorubicin resistance in chronic hypoxic HepG2 cells
Transarterial chemoembolization ( TACE )‐induced hypoxia can trigger residual liver cancer cells to present a more aggressive phenotype associated with chemoresistance, but the underlying mechanisms are still unknown. In this study, the human liver cancer cell line HepG2 was pre‐cultured in differen...
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Veröffentlicht in: | Fundamental & clinical pharmacology 2020-02, Vol.34 (1), p.41-50 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Transarterial chemoembolization (
TACE
)‐induced hypoxia can trigger residual liver cancer cells to present a more aggressive phenotype associated with chemoresistance, but the underlying mechanisms are still unknown. In this study, the human liver cancer cell line HepG2 was pre‐cultured in different oxygen environments to examine the possible mechanisms of hypoxia‐induced doxorubicin resistance. Our study showed that HepG2 cells pre‐cultured in a chronic intermittent hypoxic environment exhibited significant resistance to doxorubicin, evidenced by increased intracellular doxorubicin efflux, relatively higher cell proliferation, lower apoptosis, and decreased
DNA
damage. These changes were accompanied by high levels of
NRF
2 and
ABCB
1 under conditions of both chronic and acute hypoxia and
PARP
1 gene expression only under conditions of chronic hypoxia. Si
RNA
‐mediated silencing of
NRF
2 gene expression downregulated the expression of
ABCB
1 and increased the intracellular doxorubicin accumulation and cell apoptosis both in acute and chronic hypoxic HepG2 cells. Moreover, silencing of
PARP
1 gene expression increased the doxorubicin‐induced
DNA
damage and cell apoptosis in chronic hypoxic cells. On the basis of these findings, we concluded that
NRF
2/
ABCB
1‐mediated efflux and
PARP
1‐mediated
DNA
repair contribute to doxorubicin resistance in chronic hypoxic HepG2 cells. |
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ISSN: | 0767-3981 1472-8206 |
DOI: | 10.1111/fcp.12505 |