title: Reversal of MRP7 (ABCC10)-mediated multidrug resistance by tariquidar.
abstract: Multidrug resistance protein 7 (MRP7, ABCC10) is a recently discovered member of the ATP-binding cassette (ABC) family which are capable of conferring resistance to a variety of anticancer drugs, including taxanes and nucleoside analogs, in vivo. MRP7 is highly expressed in non-small cell lung cancer cells, and Mrp7-KO mice are highly sensitive to paclitaxel, making MRP7 an attractive chemotherapeutic target of non-small cell lung cancer. However, only a few inhibitors of MRP7 are currently identified, with none of them having progressed to clinical trials. We used MRP7-expressing cells to investigate whether tariquidar, a third generation inhibitor of P-glycoprotein, could inhibit MRP7-mediated multidrug resistance (MDR). We found that tariquidar, at 0.1 and 0.3 µM, significantly potentiated the sensitivity of MRP7-transfected HEK293 cells to MRP7 substrates and increased the intracellular accumulation of paclitaxel. We further demonstrated that tariquidar directly impaired paclitaxel efflux and could downregulate MRP7 protein expression in a concentration- and time-dependent manner after prolonged treatment. Our findings suggest that tariquidar, at pharmacologically achievable concentrations, reverses MRP7-mediated MDR through inhibition of MRP7 protein expression and function, and thus represents a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.
authors: State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, People's Republic of China.
authors: Yue-Li
authors: YL
authors: Sun
authors: Jun-Jiang
authors: JJ
authors: Chen
authors: Priyank
authors: P
authors: Kumar
authors: Kang
authors: K
authors: Chen
authors: Kamlesh
authors: K
authors: Sodani
authors: Atish
authors: A
authors: Patel
authors: Yang-Lu
authors: YL
authors: Chen
authors: Si-Dong
authors: SD
authors: Chen
authors: Wen-Qi
authors: WQ
authors: Jiang
authors: Zhe-Sheng
authors: ZS
authors: Chen
mesh_terms: D002460:Cell Line; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011804:Quinolines; C421142:ABCC10 protein, human; C402343:tariquidar
references: J Med Chem. 2003 Nov 6;46(23):4805-17
references: 14584929
references: Ann Nucl Med. 2010 Jun;24(5):403-12
references: 20361276
references: Anticancer Drugs. 2006 Mar;17(3):239-43
references: 16520651
references: J Med Chem. 2009 Feb 26;52(4):1190-7
references: 19170519
references: Cancer. 2005 Aug 15;104(4):682-91
references: 15986399
references: Nature. 2007 Apr 12;446(7137):749-57
references: 17429392
references: Res Microbiol. 2001 Apr-May;152(3-4):211-29
references: 11421270
references: Clin Cancer Res. 2000 Nov;6(11):4186-91
references: 11106230
references: ACS Chem Neurosci. 2011 Feb 16;2(2):82-9
references: 22778859
references: Clin Cancer Res. 2011 Feb 1;17(3):569-80
references: 21081657
references: Genome Res. 2001 Jul;11(7):1156-66
references: 11435397
references: Biochem Pharmacol. 2012 May 15;83(10):1340-8
references: 22342288
references: Appl Radiat Isot. 2010 Jun;68(6):1098-103
references: 20181488
references: Br J Pharmacol. 1999 Sep;128(2):403-11
references: 10510451
references: Zhongguo Fei Ai Za Zhi. 2009 Aug 20;12(8):875-8
references: 20719174
references: Br J Cancer. 1990 Jul;62(1):89-95
references: 1975203
references: AAPS J. 2009 Sep;11(3):435-44
references: 19504188
references: Nat Rev Drug Discov. 2006 Mar;5(3):219-34
references: 16518375
references: Cancer Res. 2012 Dec 15;72(24):6457-67
references: 23087055
references: Eur J Cancer. 2004 Mar;40(4):594-605
references: 14962729
references: Bioorg Med Chem Lett. 1999 Feb 22;9(4):595-600
references: 10098671
references: Eur J Cancer. 1996 Jun;32A(6):1070-81
references: 8763349
references: Cancer Res. 2001 Jan 15;61(2):749-58
references: 11212278
references: Cancer Res. 2011 May 15;71(10):3649-57
references: 21576088
references: Mutagenesis. 2012 Mar;27(2):187-96
references: 22294766
references: J Cancer Res Clin Oncol. 2008 May;134(5):597-607
references: 17932689
references: Bioorg Med Chem. 2008 Mar 1;16(5):2448-62
references: 18083034
references: Cancer Cell Int. 2005 Oct 04;5:30
references: 16202168
references: Mol Pharmacol. 2003 Feb;63(2):351-8
references: 12527806
references: Bioorg Med Chem. 2010 Aug 1;18(15):5489-97
references: 20621487
references: Cancer Sci. 2007 Sep;98(9):1303-10
references: 17608770
references: Pharmacogenomics. 2008 Jan;9(1):105-27
references: 18154452
references: J Nucl Med. 2009 Dec;50(12):1954-61
references: 19910428
references: ChemMedChem. 2012 Apr;7(4):650-62
references: 22354538
references: Cancer Biol Ther. 2006 Jan;5(1):39-47
references: 16319528
references: Expert Rev Anticancer Ther. 2007 Apr;7(4):447-59
references: 17428165
references: Mol Cancer Ther. 2008 May;7(5):1150-5
references: 18445659
references: Cancer Res. 2009 Jan 1;69(1):178-84
references: 19118001
references: Circ J. 2012;76(7):1780-91
references: 22498566
references: Bioorg Med Chem. 2009 Mar 15;17(6):2524-35
references: 19250834
references: Clin Cancer Res. 2009 May 15;15(10):3574-82
references: 19417029
references: J Natl Cancer Inst. 1998 Aug 5;90(15):1161-6
references: 9701366
references: Cancer Lett. 2013 Jan 28;328(2):307-17
references: 23063650
references: J Bioenerg Biomembr. 2001 Dec;33(6):475-9
references: 11804189
references: J Exp Ther Oncol. 2004 Oct;4(3):239-46
references: 15724843
references: Hepatology. 2012 Mar;55(3):821-32
references: 21932399
references: Curr Pharm Biotechnol. 2011 Apr;12(4):570-94
references: 21118094
references: Oncologist. 2003;8(5):411-24
references: 14530494
references: Cancer Res. 1987 Feb 15;47(4):936-42
references: 3802100
references: Cancer Res. 2004 Jul 15;64(14):4927-30
references: 15256465