Cellular pharmacology of cisplatin in relation to the expression of human copper transporter CTR1 in different pairs of cisplatin-sensitive and -resistant cells

Giovanni Luca Beretta, Laura Gatti, Stella Tinelli, Elisabetta Corna, Donato Colangelo, Franco Zunino, Paola Perego

Research output: Contribution to journalArticlepeer-review

Abstract

The molecular mechanism of cisplatin uptake remains poorly defined and impaired drug accumulation may be implicated in the acquisition of resistance to cisplatin. Thus, we used cell lines of different tumor types (ovarian carcinoma A2780 and IGROV-1, osteosarcoma U2-OS, cervix squamous cell carcinoma A431) and stable cisplatin-resistant sublines, exhibiting variable levels of resistance (between 2.5 and 18.4), to investigate the mechanisms of cellular accumulation of cisplatin. Among the resistant lines we found that reduced cisplatin uptake was a common feature and ranged between 23 and 76%. In an attempt to examine the role of human copper transporter 1 (CTR1) in cisplatin accumulation by human cells, we selected the well characterized A431 cell line and the resistant variant A431/Pt. As compared with A431/Pt cells, A431/Pt transfectants overexpressing CTR1 (3.4-fold) exhibited increased uptake of copper, thereby supporting the expression of a functional transporter. However, no changes in cisplatin uptake and cellular sensitivity to drug were observed. Also overexpression of CTR1 in A431 cells did not produce modulation of cisplatin accumulation. An analysis of the expression of other factors that could affect drug accumulation indicated that A431/Pt cells displayed increased expression of ATPase, Cu2+ transporting, alfa polypeptide. In conclusion, our results indicate that the overexpression of a functional CTR1 in a human cell line characterized by impaired cisplatin uptake fails (a) to restore cellular drug accumulation to the level of the parental cell line and (b) to modulate cisplatin sensitivity. Our data are consistent with the interpretation that the defects in cellular accumulation by resistant cells are not mediated by expression of CTR1, that plays a marginal role, if any, in cisplatin transport.

Original languageEnglish
Pages (from-to)283-291
Number of pages9
JournalBiochemical Pharmacology
Volume68
Issue number2
DOIs
Publication statusPublished - Jul 15 2004

Keywords

  • ATP7A
  • ATP7B
  • ATPase, Cu transporting, beta polypeptide
  • ATPase, Cu transporting, alfa polypeptide
  • cisplatin
  • copper transporter 1
  • copper transporter 2
  • CTR1
  • CTR2
  • DDP
  • PBS
  • phosphate-buffered saline
  • resistance index
  • RI

ASJC Scopus subject areas

  • Pharmacology

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