In Vitro Characterization of Renal Drug Transporter Activity in Kidney Cancer.
drug transporter
nephrotoxicity
proximal tubule epithelial cells
renal cell carcinoma
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
05 Sep 2022
05 Sep 2022
Historique:
received:
10
08
2022
revised:
29
08
2022
accepted:
30
08
2022
entrez:
9
9
2022
pubmed:
10
9
2022
medline:
14
9
2022
Statut:
epublish
Résumé
The activity of drug transporters is central to the secretory function of the kidneys and a defining feature of renal proximal tubule epithelial cells (RPTECs). The expression, regulation, and function of these membrane-bound proteins is well understood under normal renal physiological conditions. However, the impact of drug transporters on the pathophysiology of kidney cancer is still elusive. In the present study, we employed different renal cell carcinoma (RCC) cell lines and a prototypical non-malignant RPTEC cell line to characterize the activity, expression, and potential regulatory mechanisms of relevant renal drug transporters in RCC in vitro. An analysis of the uptake and efflux activity, the expression of drug transporters, and the evaluation of cisplatin cytotoxicity under the effects of methylation or epidermal growth factor receptor (EGFR) inhibition showed that the RCC cells retained substantial drug transport activity. In RCC cells, P-glycoprotein was localized in the nucleus and its pharmacological inhibition enhanced cisplatin toxicity in non-malignant RPTECs. On the other hand, methylation inhibition enhanced cisplatin toxicity by upregulating the organic cation uptake activity in RCC cells. Differential effects of methylation and EGFR were observed in transporter expression, showing regulatory heterogeneity in these cells. Interestingly, the non-malignant RPTEC cell line that was used lacked the machinery responsible for organic cation transport, which reiterates the functional losses that renal cells undergo in vitro.
Identifiants
pubmed: 36077583
pii: ijms231710177
doi: 10.3390/ijms231710177
pmc: PMC9456511
pii:
doi:
Substances chimiques
Cations
0
Membrane Transport Proteins
0
ErbB Receptors
EC 2.7.10.1
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
Références
Toxicol Rep. 2014;1:231-242
pubmed: 25126521
Clin Pharmacol Ther. 2018 Nov;104(5):890-899
pubmed: 30091177
Kidney Int Suppl. 2005 Dec;(99):S46-51
pubmed: 16336576
Sci Rep. 2016 Jul 20;6:29930
pubmed: 27435027
Cells. 2019 Feb 28;8(3):
pubmed: 30823476
Drug Resist Updat. 2021 Dec;59:100796
pubmed: 34953682
Mol Pharm. 2016 Mar 7;13(3):933-44
pubmed: 26871298
Expert Opin Drug Metab Toxicol. 2021 Jun;17(6):635-653
pubmed: 33896325
Mol Pharm. 2019 Feb 4;16(2):510-517
pubmed: 30656943
Curr Drug Deliv. 2004 Jan;1(1):27-42
pubmed: 16305368
Curr Drug Targets. 2014;15(14):1322-30
pubmed: 25479544
Front Oncol. 2020 Oct 26;10:576559
pubmed: 33194688
Biomedicines. 2021 Apr 14;9(4):
pubmed: 33919957
Sci Rep. 2019 Jun 27;9(1):9332
pubmed: 31249353
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14298-302
pubmed: 12370430
Int J Mol Sci. 2021 Aug 14;22(16):
pubmed: 34445451
Nephron Exp Nephrol. 2007;107(2):e47-56
pubmed: 17804913
Nature. 2019 Nov;575(7782):299-309
pubmed: 31723286
Cancers (Basel). 2021 Jun 01;13(11):
pubmed: 34206026
J Vis Exp. 2011 Apr 24;(50):
pubmed: 21540825
Biomed Pharmacother. 2013 Jul;67(6):497-502
pubmed: 23602050
Channels (Austin). 2021 Dec;15(1):375-385
pubmed: 33825659
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700-4
pubmed: 7937876
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
World J Oncol. 2020 Jun;11(3):79-87
pubmed: 32494314
Cancer. 2012 Mar 1;118(5):1268-75
pubmed: 22161775
J Pathol Transl Med. 2018 Sep;52(5):323-330
pubmed: 30121971
Front Pharmacol. 2022 Jan 13;12:802539
pubmed: 35095509
Biomedicines. 2021 Nov 24;9(12):
pubmed: 34944574
PLoS Biol. 2018 Apr 16;16(4):e2002907
pubmed: 29659562
Med Oncol. 2015 Jan;32(1):419
pubmed: 25487445
Trends Pharmacol Sci. 2006 Nov;27(11):587-93
pubmed: 16996621
Genes Chromosomes Cancer. 1998 Jul;22(3):200-9
pubmed: 9624531
Sci Transl Med. 2016 Jul 20;8(348):348ra97
pubmed: 27440728
Mol Pharmacol. 2008 Oct;74(4):1084-91
pubmed: 18612079
Molecules. 2014 Aug 25;19(9):13061-75
pubmed: 25157469
ChemMedChem. 2012 Apr;7(4):650-62
pubmed: 22354538
Int J Mol Sci. 2019 Oct 24;20(21):
pubmed: 31653114
Blood. 2000 May 1;95(9):2897-904
pubmed: 10779437
Biol Sex Differ. 2015 Mar 02;6:4
pubmed: 25750709
Mol Pharm. 2017 Jun 5;14(6):2147-2157
pubmed: 28493713
Br J Cancer. 2020 Feb;122(4):465-472
pubmed: 31831859
Front Physiol. 2014 Mar 20;5:108
pubmed: 24688472
Kidney Int. 2010 May;77(9):809-15
pubmed: 20147887
Drug Resist Updat. 2017 Jan;30:15-27
pubmed: 28363332
Adv Chronic Kidney Dis. 2016 Mar;23(2):76-81
pubmed: 26979146
Pharmacol Ther. 2021 Jan;217:107647
pubmed: 32758646
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
Arch Toxicol. 2019 Dec;93(12):3397-3418
pubmed: 31664498
Clin J Am Soc Nephrol. 2015 Nov 6;10(11):2039-49
pubmed: 26490509
J Inorg Biochem. 2012 Nov;116:1-10
pubmed: 23010323