Abstract
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.
Highlights
Multidrug resistance (MDR) to chemotherapeutic drugs could be found in various types of cancer cells (Fletcher et al, 2010)
The results indicated that the MDR reversal mechanism of Y6 was not induced by altering the localization of ABC subfamily G member 2 (ABCG2)
The results indicated that the MDR reversal mechanism of Y6 was not relative with the expression level and subcellular localization of ABCG2
Summary
Multidrug resistance (MDR) to chemotherapeutic drugs could be found in various types of cancer cells (Fletcher et al, 2010). ABCG2 transporter is distributed in the plasma membrane It is highly expressed in the colon epithelium, the apical surface of small intestines, the canalicular membrane of liver and bile duct, cortical tubules of the kidney and prostate epithelium, and at the luminal surfaces of microvessel endothelium of human brain (Maliepaard et al, 2001; Fetsch et al, 2006). Such distribution results in alteration of the absorption, distribution, metabolism, and elimination of drugs since ABCG2 performs compound transmembrane transport on secretory surfaces of organs. ABCG2 could transport a variety of anti-neoplastic drugs such as mitoxantrone, topotecan, irinotecan, doxorubicin, daunorubicin, 9-aminocamptothecin, and epirubicin as its substrates (Doyle and Ross, 2003)
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