The ABCG2 multidrug transporter is knownto confer cancer cell multidrug resistance by causing the effluxof anticancer drugs; therefore, selective inhibitors have thepotential to improve chemotherapeutic treatments. Here,various methoxy derivatives of resveratrol are shown to bepotent inhibitors of mitoxantrone efflux by ABCG2: among aseries of 11 derivatives, compound 9 (3,5,3′,4′-tetramethoxytrans-stilbene) had an IC50 of 0.16 μM and showed a maximalinhibition of 75%, as measured by flow cytometry. It was nottransported, as shown by HPLC fractionation and mass spectrometry titration and the lack of any cross-resistance in cell survivalexperiments. Compound 9 had a very low intrinsic cytotoxicity and was able to chemosensitize the growth of resistant ABCG2-transfected HEK293 cells at submicromolar concentrations. Drug-efflux inhibition was specific for ABCG2 since very low effectswere observed with ABCB1 and ABCC1. The action mechanism of compound 9 was different from that of GF120918, whichproduced a complete and partly competitive but not ABCG2-specific inhibition, since ABCB1 was even more strongly inhibited.The two inhibitors also displayed different effects on the ABCG2 vanadate-sensitive ATPase activity, suggesting that they eitherbound to distinct sites or induced different conformational changes. Mitoxantrone efflux was fully inhibited by combining lowconcentrations of compound 9 with either GF120918 or a transport substrate such as prazosin or nilotinib. We conclude thatmethoxy derivatives of stilbene are good candidates for investigating future in vivo modulation of ABCG2 drug-efflux activity.

Methoxy stilbenes as potent, specific, untransported, and noncytotoxic inhibitors of breast cancer resistance protein

TRINGALI, Corrado;
2012-01-01

Abstract

The ABCG2 multidrug transporter is knownto confer cancer cell multidrug resistance by causing the effluxof anticancer drugs; therefore, selective inhibitors have thepotential to improve chemotherapeutic treatments. Here,various methoxy derivatives of resveratrol are shown to bepotent inhibitors of mitoxantrone efflux by ABCG2: among aseries of 11 derivatives, compound 9 (3,5,3′,4′-tetramethoxytrans-stilbene) had an IC50 of 0.16 μM and showed a maximalinhibition of 75%, as measured by flow cytometry. It was nottransported, as shown by HPLC fractionation and mass spectrometry titration and the lack of any cross-resistance in cell survivalexperiments. Compound 9 had a very low intrinsic cytotoxicity and was able to chemosensitize the growth of resistant ABCG2-transfected HEK293 cells at submicromolar concentrations. Drug-efflux inhibition was specific for ABCG2 since very low effectswere observed with ABCB1 and ABCC1. The action mechanism of compound 9 was different from that of GF120918, whichproduced a complete and partly competitive but not ABCG2-specific inhibition, since ABCB1 was even more strongly inhibited.The two inhibitors also displayed different effects on the ABCG2 vanadate-sensitive ATPase activity, suggesting that they eitherbound to distinct sites or induced different conformational changes. Mitoxantrone efflux was fully inhibited by combining lowconcentrations of compound 9 with either GF120918 or a transport substrate such as prazosin or nilotinib. We conclude thatmethoxy derivatives of stilbene are good candidates for investigating future in vivo modulation of ABCG2 drug-efflux activity.
File in questo prodotto:
File Dimensione Formato  
Methoxy stilbenes inhibitors breast cancer resistance protein_2012.pdf

solo gestori archivio

Tipologia: Versione Editoriale (PDF)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 324.73 kB
Formato Adobe PDF
324.73 kB Adobe PDF   Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/58331
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 45
  • ???jsp.display-item.citation.isi??? 43
social impact