Y₆, an Epigallocatechin Gallate Derivative, Reverses ABCG2-Mediated Mitoxantrone Resistance

Multidrug resistance is reported to be related to the transmembrane transportation of chemotherapeutic drugs by adenosine triphosphate-binding cassette (ABC) transporters. ABC subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which have been implicated as a key contributor to the development of multidrug resistance in cancers. A new epigallocatechin gallate derivative, Y₆ was synthesized in our group. Our previous study revealed that Y₆ increased the sensitivity of drug-resistant cells to doxorubicin, which was associated with down-regulation of P-glycoprotein expression. In this study, we further determine whether Y₆ could reverse ABCG2-mediated multidrug resistance. Results showed that, at non-toxic concentrations, Y₆ significantly sensitized drug-selected non-small cell lung cancer cell line NCI-H460/MX20 to substrate anticancer drugs mitoxantrone, SN-38, and topotecan, and also sensitized ABCG2-transfected cell line HEK293/ABCG2-482-R2 to mitoxantrone and SN-38. Further study demonstrated that Y₆ significantly increased the accumulation of [³H]-mitoxantrone in NCI-H460/MX20 cells by inhibiting the transport activity of ABCG2, without altering the expression levels and the subcellular localization of ABCG2. Furthermore, Y₆ stimulated the adenosine triphosphatase activity with a concentration-dependent pattern under 20 μM in membranes overexpressing ABCG2. In addition, Y₆ exhibited a strong interaction with the human ABCG2 transporter protein. Our findings indicate that Y₆ may potentially be a novel reversal agent in ABCG2-positive drug-resistant cancers.