Original ArticleThe dopamine D3 receptor antagonists PG01037, NGB2904, SB277011A, and U99194 reverse ABCG2 transporter-mediated drug resistance in cancer cell lines

- D3 antagonists have structural similarities with bcr-abl TKIs (ABCG2 modulators).
- D3 antagonists reverse ABCG2 mediated multidrug resistance in cancer cells.
- D3 antagonists inhibit ABCG2 function and downregulate its expression.
- D3 antagonists bind with high affinity to ABCG2 in silico.
- D3 antagonists synergize mitoxantrone and doxorubicin anticancer activity.

The ATP - binding cassette (ABC) family G2 (ABCG2) transporters are known to produce multidrug resistance (MDR) in cancer, thereby limiting the clinical response to chemotherapy. Molecular modeling data indicated that certain dopamine (DA) D3 receptor antagonists had a significant binding affinity for ABCG2 transporter. Therefore, in this in vitro study, we determined the effect of the D3 receptor antagonists PG01037, NGB2904, SB277011A, and U99194 on MDR resulting from the overexpression of ABCG2 transporters. The D3 receptor antagonists, at concentrations >100 μM, did not significantly affect the viability of H460-MX20, S1M1-80, A549-MX10 or wild type ABCG2 overexpressing (HEK293-R2) cells. However, at concentrations ranging from 0.01 to 10 μM, the D3 receptor antagonists PG01037, NGB2904, SB-277011A, and U99194 significantly increased the efficacy of the anticancer drugs mitoxantrone and doxorubicin in ABCG2-overexpressing MDR cells. Efflux studies indicated that both PG01037 and NGB2904, at a concentration of 5 μM, significantly decreased the efflux of rhodamine 123 from H460-MX20 cells. Interestingly, 5 μM of PG01037 or NGB2904 significantly decreased the expression levels of the ABCG2 protein, suggesting that these compounds inhibit both the function and expression of ABCG2 transporters at non-toxic concentrations.