NRF2/ABCB1‐mediated efflux and PARP1‐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 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 NRF2 and ABCB1 under conditions of both chronic and acute hypoxia and PARP1 gene expression only under conditions of chronic hypoxia. SiRNA‐mediated silencing of NRF2 gene expression downregulated the expression of ABCB1 and increased the intracellular doxorubicin accumulation and cell apoptosis both in acute and chronic hypoxic HepG2 cells. Moreover, silencing of PARP1 gene expression increased the doxorubicin‐induced DNA damage and cell apoptosis in chronic hypoxic cells. On the basis of these findings, we concluded that NRF2/ABCB1‐mediated efflux and PARP1‐mediated DNA repair contribute to doxorubicin resistance in chronic hypoxic HepG2 cells.