Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1

Abstract

Xanthohumol (XN) is a well-known prenylated flavonoid found in Humulus lupulus L. It is involved in several pharmacological activities, including the sensitization of doxorubicin-resistant breast cancer (MCF-7/ADR) cells to doxorubicin (DOX) through a reduction in cell viability and stemness. In the present study, we revealed another mechanism to further explain the reverse of the drug resistance of XN. In the MCF-7/ADR cell line, we found that XN inhibited the efflux functions of ATP-binding cassette subfamily B member 1 (ABCB1). We also observed that XN was a substrate of ABCB1 and stimulated its ATPase activity. Moreover, our results revealed that XN showed a synergic effect with the ABCB1 substrate colchicine (COL) in the MCF-7/ADR cell line. Further, we showed that XN bound to the central transmembrane domain (TMD) site, overlapping with the DOX binding site. This mechanism was supported by molecular modeling and simulation data, which revealed that XN bound to the ABCB1 transmembrane domain, where doxorubicin also binds, and its binding affinity was stronger than that of doxorubicin, resulting in less protein and ligand position fluctuation. These results support the XN-induced reversal of drug resistance via the inhibition of ABCB1-mediated transport of doxorubicin, stimulating ABCB1 ATPase activity and acting as a substrate of ABCB1.

Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1

“…Some interactions of the lead compounds with Phe-343, Gln-347, Met-986 and Gln-990 have also been observed previously in structures solved with the transport substrates taxol [15] and vincristine [16]. Moreover, molecular docking simulations have previously indicated hydrophobic interaction between inhibitors and the ABCB1 residues Phe-303, Phe-343 and Ile-340, π-π stacking with Trp-232, Tyr-307 and Phe-303, and hydrogen bonding with Tyr-310, Gln-725, Glu-875, Tyr-953 and Gln-990 [15,20,40,52,[54][55][56]. Of these amino acids, only Trp-232, Tyr-310 and Tyr-953 are absent from interaction with any of our four lead compounds, although the interaction with Tyr-307 is predicted to be hydrophobic.…”

Molecular docking and simulation studies of natural compounds ofVitex negundoL. against papain-like protease (PLpro) of SARS CoV-2 (coronavirus) to conquer the pandemic situation in the world

“…RESPA integrator was used to calculate the bonding interactions for a time step 2 fs (Stuart et al, 1996). All other parameters were associated in the settings followed as described elsewhere (Liu et al, 2018). After the final production run, the simulation trajectories of apo protein and complexed with ligands were analyzed for final outcome of RMSD and RMSF, ligand RMSF, derived from the simulation.…”

Design, Synthesis, and Biological Evaluation of Marine Lissodendrins B Analogues as Modulators of ABCB1-Mediated Multidrug Resistance

“…In our previous screening work for ABCB1 inhibitors, we found that cardiotonic steroid compounds display anti-DOX resistance activity by stimulating ABCB1 ATPase activity [ 35 ]. Flavonoid compounds, e.g., xanthohumol and isoxanthohumol, also act as ABCB1 substrates and reverse MDR in MCF-7/ADR cells [ 36 , 37 ]. Other research groups also showed that tyrosine kinase inhibitors modulate ABCB1 functions through stimulating the ATPase activity [ 38 ].…”