B-9-8, a Novel Harman Dimer, Reverses ABCG2-mediated Chemotherapeutic Drug Resistance

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.

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.

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.

The results showed that B-9-8 could significantly increase the sensitivity to 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.

B-9-8, as a novel harman dimer, exhibits its reversal activity against ABCG2- mediated multidrug resistance without obvious cytotoxicity. Its actions of inhibiting ABCG2 efflux function and down-regulating the protein expression of ABCG2 are crucial for overcoming drug resistance. This makes B-9-8 a possible candidate drug for combined chemotherapy. Its inhibitory effect of ATPase activity and the strong affinity to ABCG2 further demonstrate the potential of B-9-8 as a targeted modulator for drug resistance.

Our findings indicated that B-9-8 could reverse ABCG2-mediated MDR as a potential and reversible modulator in combination with conventional chemotherapeutic drugs.