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

Abstract

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.

• Authors: Noor Hussein, Haneen Amawi, Chandrabose Karthikeyan, F Scott Hall, Roopali Mittal, Piyush Trivedi, Charles R Ashby Jr, Amit K Tiwari
• Journal: Cancer letters (Cancer Lett) Vol. 396 Pg. 167-180 (06 28 2017) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 28323029 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Benzamides
• Fluorenes
• N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide
• NGB 2904
• Neoplasm Proteins
• Nitriles
• Piperazines
• Pyridines
• Receptors, Dopamine D3
• SB 277011
• Tetrahydroisoquinolines
• Doxorubicin
• Mitoxantrone

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2 (antagonists & inhibitors, biosynthesis, metabolism)
• Benzamides (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, metabolism)
• Down-Regulation (drug effects)
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Synergism
• Fluorenes (pharmacology)
• HEK293 Cells
• Humans
• Lung Neoplasms (drug therapy, metabolism)
• Mitoxantrone (pharmacology)
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, metabolism)
• Nitriles (pharmacology)
• Piperazines (pharmacology)
• Pyridines (pharmacology)
• Receptors, Dopamine D3 (antagonists & inhibitors)
• Tetrahydroisoquinolines (pharmacology)