Mifepristone potentiates etoposide toxicity in Hep G2 cells by modulating drug transport
Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
30217652
DOI
10.1016/j.tiv.2018.09.005
PII: S0887-2333(18)30548-4
Knihovny.cz E-zdroje
- Klíčová slova
- ABC transporters, Etoposide, Hep G2 cells, RU486, xCELLigence,
- MeSH
- ABC transportér z rodiny G, člen 2 antagonisté a inhibitory MeSH
- biologický transport účinky léků MeSH
- buňky Hep G2 MeSH
- buňky K562 MeSH
- etoposid farmakologie MeSH
- fytogenní protinádorové látky farmakologie MeSH
- kaspasa 3 metabolismus MeSH
- lidé MeSH
- mifepriston farmakologie MeSH
- nádorové proteiny antagonisté a inhibitory MeSH
- P-glykoproteiny antagonisté a inhibitory MeSH
- protein X asociovaný s bcl-2 metabolismus MeSH
- synergismus léků MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ABC transportér z rodiny G, člen 2 MeSH
- ABCB1 protein, human MeSH Prohlížeč
- ABCG2 protein, human MeSH Prohlížeč
- BAX protein, human MeSH Prohlížeč
- CASP3 protein, human MeSH Prohlížeč
- etoposid MeSH
- fytogenní protinádorové látky MeSH
- kaspasa 3 MeSH
- mifepriston MeSH
- nádorové proteiny MeSH
- P-glykoproteiny MeSH
- protein X asociovaný s bcl-2 MeSH
Etoposide is a well-known and widely used anticancer drug that displays several side effects. In addition, tumors often acquire resistance to this drug. Our aim is to develop a combination therapy that would augment toxicity of etoposide in malignant cells. Based on literature and our experiments, we selected mifepristone (RU486) as a potential supporting molecule that is able to enhance etoposide toxicity against cancer cells. All experiments were performed with Hep G2 cells, a well-known and described human hepatocellular carcinoma cell line. By using xCELLigence system, we demonstrated that mifepristone enhances toxicity of etoposide in a dose dependent manner with concomitant caspase-3 activity. We evaluated upregulation of Bax because mifepristone was demonstrated to modulate proapoptotic Bax protein expression. Our data show only weak and not statistically significant increase of Bax expression. On the other hand, we show that mifepristone increases etoposide toxicity via inhibition of ABC transporters, coupled with significant increase of intracellular etoposide concentration. In conclusion, we demonstrate that mifepristone has a synergistic effect with etoposide treatment in the Hep G2 cells and that the effect is related to ABC transporters inhibition.
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