The dopamine D3receptor antagonists PG01037, NGB2904, SB277011A, and U99194 reverse ABCG2 transporter-mediated drug resistance in cancer cell lines.
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) D3receptor antagonists had a significant binding affinity for ABCG2 transporter. Therefore, in this in vitro study, we determined the effect of the D3receptor antagonists PG01037, NGB2904, SB277011A, and U99194 on MDR resulting from the overexpression of ABCG2 transporters. The D3receptor 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 D3receptor 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.
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, OH 43614, USA.
Noor
N
Hussein
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, OH 43614, USA.
Haneen
H
Amawi
School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, MP 462036, India.
Chandrabose
C
Karthikeyan
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, OH 43614, USA.
F Scott
FS
Hall
Pediatric Gastroenterology, OU Medical Center, Children's Ave, Oklahoma City, OK 73104, USA.
Roopali
R
Mittal
School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, MP 462036, India.
Piyush
P
Trivedi
Pharmaceutical Sciences, College of Pharmacy, St. John's University, Queens, NY 11432, USA. Electronic address: cnsratdoc@optonline.net.
Charles R
CR
Ashby
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, OH 43614, USA. Electronic address: amit.tiwari@utoledo.edu.
Amit K
AK
Tiwari
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005449:Fluorenes / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D001549:Benzamides; D005449:Fluorenes; C497150:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide; C116818:NGB 2904; D009363:Neoplasm Proteins; D009570:Nitriles; D010879:Piperazines; D011725:Pyridines; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; D008942:Mitoxantrone
ABCG2-transporters; D(3) receptor antagonists; Multidrug resistance; NGB2904; PG01037; SB277011A