Prenylflavonoid Isoxanthohumol Sensitizes MCF-7/ADR Cells to Doxorubicin Cytotoxicity via Acting as a Substrate of ABCB1

Ming Liu,Xin Zhou,Wei Zhang,Ming Li,Weiyi Zhang,Jinlai Miao

doi:10.3390/toxins9070208

Abstract

Isoxanthohumol is a unique prenylflavonoid with the highest content in beer. Isoxanthohumol has multiple bioactivities and has recently received considerable attention in the scientific community. Nonetheless; its effect on drug resistant cancer cells has rarely been studied. In this paper; we investigated the synergistic effect of isoxanthohumol and doxorubicin on doxorubicin resistant MCF-7/ADR cells. Our results showed that isoxanthohumol sensitized the cytotoxic effect of doxorubicin on MCF-7/ADR cells via increased proliferation inhibition and apoptosis stimulation. Molecular mechanism studies further demonstrated that isoxanthohumol inhibited ABCB1-mediated doxorubicin efflux; stimulated the ATPase activity of ABCB1 (ATP-binding cassette sub-family B member 1); and acted as an ABCB1 substrate. Molecular docking results suggested that isoxanthohumol bound to the central transmembrane domain of ABCB1 and its binding site overlapped with the doxorubicin binding site. The present studies demonstrated that isoxanthohumol was a competitive ABCB1 inhibitor which reversed ABCB1-mediated doxorubicin resistance in MCF-7/ADR cells; and therefore could be further developed to help with overcoming ABCB1-mediated drug resistance.

Highlights

In addition to radiation therapy and tumor resection, chemotherapy, for example, doxorubicin (DOX) treatment, still plays a major role in breast cancer treatment
We revealed IXN could enhance the efficiency of DOX on MCF-7/ADR cells by competitively inhibiting the ATP-binding cassette sub-family B member 1 (ABCB1) transporting function and increasing the intracellular content of DOX
We revealed the prenylflavonoid compound IXN to be a substrate of ABCB1, which improves the understanding about the prenylflavonoids regarding their novel bioavailability in ATP-binding cassette (ABC)-transporter-mediated drug interaction and drug resistance

Summary

Introduction

In addition to radiation therapy and tumor resection, chemotherapy, for example, doxorubicin (DOX) treatment, still plays a major role in breast cancer treatment. The clinical efficacy of DOX is challenged by a major obstacle represented by the development of multidrug resistance (MDR) [1]. In the case of DOX treatment in breast cancer, MDR reduces intracellular drug accumulation by activating the efflux of chemotherapeutic agents through membrane transporters, such as the ATP-binding cassette (ABC) proteins, which mainly include p-glycoprotein (ATP-binding cassette sub-family B member 1)), the multidrug resistance protein 1 (ATP-binding cassette sub-family C member 1)), and the breast cancer resistance proteins (BCRP, ABCG2 (ATP-binding cassette sub-family G member 2)) [2]. Much effort has been devoted to searching for phytochemicals that can inhibit ABC transporters and have better safety profiles in the treatment of cancer [4]

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Discussion

Conclusion