Reversal of multidrug resistance of hepatocellular carcinoma cells by metformin through inhibitingNF-κBgene transcription

Abstract

AIM:To interfere with the activation of nuclear factor-κB (NF-κB) with metformin and explore its effect in reversing multidrug resistance (MDR) of hepatocellular carcinoma (HCC) cells. METHODS:Expression of P-glycoprotein (P-gp) and NF-κB in human HepG2 or HepG2/adriamycin (ADM) cells RESULTS: P-gp overexpression in HepG2 and HepG2/ ADM cells was closely related to mdr1 mRNA (3.310 ± 0.154) and NF-κB mRNA (2.580 ± 0.040) expression. NF-κB gene transcription was inhibited by specific siRNA with significant down-regulation of P-gp and enhanced HCC cell chemosensitivity to doxorubicin. After pretreatment with metformin, HepG2/ADM cells were sensitized to doxorubicin and P-gp was decreased through the NF-κB signaling pathway. The synergistic effect of metformin and NF-κB siRNA were found in HepG2/ADM cells with regard to proliferation inhibition, cell cycle arrest and inducing cell apoptosis. Core tip: Metformin might target AMP-activated protein kinase mammalian target of rapamycin pathway, suppress hypoxia-inducible factor-1α and transcriptionally down-regulate P-glycoprotein (P-gp) and multidrug resistance (MDR)-associated protein 1, suggesting that metformin may reverse MDR by targeting the AMPactivated protein kinase/mammalian target of rapamycin/ hypoxia-inducible factor-1α/P-gp and MDR-associated protein 1 pathways. In the present study, HepG2/ADM cells pretreated with metformin were sensitized to doxorubicin and P-gp was decreased through the nuclear factor-κB (NF-κB) signaling pathway. The synergistic effects were found in the cells with regard to proliferation inhibition, cell cycle arrest and inducing apoptosis, and inhibiting P-gp expression via the NF-κB signaling pathway effectively reversed MDR by down-regulating MDR1/P-gp expression. CONCLUSION:

NIK‑ and IKKβ‑binding protein contributes to gastric cancer chemoresistance by promoting epithelial‑mesenchymal transition through the NF‑κB signaling pathway

“…In the present study, it was confirmed that the chemo-refractory phenotype was reversed by EGb 761 by suppressing NIBP, the NF-κB signaling pathway and EMT. Research suggests that the activation of NF-κB weakens the effects of chemotherapy drugs on tumor cells and that it is associated with enhanced multi-drug resistance (23,24). Furthermore, cisplatin results in acquisition of chemoresistance via triggering EMT through the NF-κB signaling pathway (12,25).…”

Synergistic effect of farnesyl transferase inhibitor lonafarnib combined with chemotherapeutic agents against the growth of hepatocellular carcinoma cells

“…Kim et al first described that a combination of tamoxifen and cyclosporin A showed significant synergism on the sensitivity to doxorubicin of both low and high ABCB1-expressing HCC cell lines [ 16 ]. Recently, Wu et al also reported that metformin, by silencing NF-κB signaling, could effectively reverse MDR in HCC cells by the downregulation of ABCB1 expression [ 17 ]. Even though these strategies show some positive effects on MDR reversal, the innate toxicities of these compounds, for example, off-target effects from antisense RNA constructs, and severe side effects caused by these compounds must be carefully considered [ 18 ].…”

Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells

“…Lately, several studies have reported that metformin not only inhibits cell proliferation in breast, gastric, ovarian, and small cell lung cancers [8][9][10][11] but also potentiates the cytotoxic effect of some TKIs in bladder, colorectal, and non-small cell lung cancer [12][13][14]. In addition, it is also known to reverse multidrug resistance by regulating cancer stem cell population or signaling [15][16][17]. However, the effects of metformin on CML have not been elucidated.…”