Dihydroartemisinin Sensitizes Mutant p53 (R248Q)-Expressing Hepatocellular Carcinoma Cells to Doxorubicin by Inhibiting P-gp Expression

Abstract

Mutant p53 (R248Q) induces doxorubicin (ADM) resistance in hepatocellular carcinoma (HCC). Dihydroartemisinin (DHA) can synergistically enhance anticancer effect of many chemotherapeutic agents. However, whether DHA could increase therapeutic efficacy of ADM in p53 (R248Q)-expressing HCC cells remains unknown. In the present study, we established mutant p53 (R248Q)-expressing Hep3B cells to study the effect and mechanism of DHA on ADM resistance and the synergistic effect of DHA with ADM. We found that P-gp was highly expressed in p53 (R248Q)-expressing Hep3B cells. As a result, cells expressing p53 (R248Q) displayed higher cell viability and lower cell apoptosis level upon ADM treatment. Meanwhile, phosphorylation levels of ERK1/2 and p65 were elevated in p53 (R248Q)-expressing Hep3B cells. However, combination of DHA and ADM treatment decreased cell viability and elevated cell apoptosis level in p53 (R248Q)-expressing Hep3B cells. Molecular dynamics simulations showed that DHA had the potential to bind with mutant p53 (R248Q) protein. Furthermore, DHA treatment decreased P-gp expression and inhibited phosphorylation levels of ERK1/2 and p65 in p53 (R248Q)-expressing Hep3B cells. Finally, DHA treatment could significantly reduce ADM efflux in p53 (R248Q)-expressing cells. Our results indicate that DHA could decrease P-gp expression via inhibiting the p53 (R248Q)-ERK1/2-NF-κB signaling pathway, which eventually confers sensitization of p53 (R248Q)-expressing HCC cells to ADM. Our study provides evidence for the potential application of DHA and ADM combination in treatment of mutant p53 (R248Q)-harbored HCC.

Frontier progress of the combination of modern medicine and traditional Chinese medicine in the treatment of hepatocellular carcinoma

“…And ginger extract reduced malondialdehyde and tumor necrosis factor (TNF)-α to improve the cardiotoxicity caused by DOX [ 58 , 59 ]. Dihydroartemisinin, Y 6 (epigallocatechin gallate derivative) and astragalus polysaccharides overcame the drug resistance of DOX and restored its sensitivity in the treatment of HCC, while astragalus polysaccharides could regulate the expression level of serum cytokines in mice bearing H22 tumor and inhibit tumor progression [ 60 – 62 ]. Rosmarinic acid, cinobufacini and quercetin separately synergized DOX to induce the apoptosis of hepatoma cells and boost the therapeutic effect of DOX [ 63 – 65 ].…”

Dihydroartemisinin as a Sensitizing Agent in Cancer Therapies

“…The higher expression of P-gp on the endothelial cell surface could reduce the penetration of chemotherapy drugs to specific sites. DHA could restrain the expression of P-gp by inhibiting the p53 (R248Q)-ERK1/2-NF-κB signaling pathway, so that liver cancer cells embedding p53 (R248Q) are sensitized to doxorubicin, 31 and reverse chemotherapy resistance. DHA elevated the sensitivity of human colon cancer resistant cells HCT8/ADR to DOX trough down-regulating the expression of Bcl-xl and inducing autophagy.…”

Anti-malarial drug: the emerging role of artemisinin and its derivatives in liver disease treatment

“…Yang et al showed that mutant p53 (R248Q) induced doxorubicin (ADM) resistance in Hep3B by increasing ADM efflux, AKT, extracellular signal-regulated protein kinases (ERK)1/2, and p65 phosphorylation and P-glycoprotein (P-gp) expression [ 94 ]. However, DHA enhanced the pro-apoptotic effects of ADM in Hep3B cells with mutant p53 (R248Q) synergistically, and it was indicated that DHA suppressed the P-gp expression by monitoring the p53 (R248Q)-ERK1/2-NF-κB pathway [ 95 ]. Taken together, these studies demonstrated that artemisinins can enhance therapeutic effectiveness of chemotherapeutic drugs through various mechanisms.…”