Background::Multidrug resistance (MDR) in cancer is a major obstacle to achieving
success in clinical chemotherapy. It has been observed that overexpression of ATP-Binding
Cassette (ABC) transporters plays a crucial role in MDR.
Objective::This study aimed to find an effective resistance-reversed agent of ABC transporter.
A series of new β-carboline derivatives have been synthesized and are being applied in various
invention patents. One of these is B-9-8, a novel harman dimer, which was synthesized to conduct
a series of experiments.
Methods::In this study, we investigated whether B-9-8 could reverse ABCG2-mediated drug
resistance by using MTT assay, [3H]-mitoxantrone accumulation/efflux assay, western blot
analysis, immunofluorescence analysis, ATPase assay, and molecular modeling assay.
Results::The results showed that B-9-8 could significantly increase the sensitivity of mitoxantrone,
SN-38, and topotecan and effectively overcame drug resistance at non-toxic concentrations
in ABCG2-overexpressing cells. Further studies showed that B-9-8 increased the intracellular
accumulation of [3H]-mitoxantrone by suppressing the efflux function of ABCG2 in
ABCG2-overexpressing cells. B-9-8 could down-regulate the ABCG2 protein expression but
did not change the subcellular localization of ABCG2. ATPase analysis indicated that B-9-8
inhibited the ATPase activity of ABCG2 in a concentration-dependent manner. In the molecular
docking analysis, B-9-8 demonstrated a strong interaction with the human ABCG2 transporter
protein.
Conclusion::Our findings indicated that B-9-8 could reverse ABCG2-mediated MDR as a potential
and reversible modulator in combination with conventional chemotherapeutic drugs.
