Overcoming multidrug drug resistance in P-glycoprotein/MDR1-overexpressing cell lines by ecteinascidin 743

Atsuko Kanzaki, Yuji Takebayashi, Xiao Qin Ren, Hitoshi Miyashita, Shiro Mori, Shin Ichi Akiyama, Yves Pommier

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Ecteinascidin 743 (Et-743) is a novel anticancer agent forming covalent guanine adducts at specific sites in the DNA minor groove. Et-743 has a unique mechanism of action because it kills cancer cells by poisoning transcription-coupled nucleotide excision repair. Recent studies suggested a complex relationship between P-glycoprotein (P-gp)/MDR1 and Et-743. On one hand, Et-743 was reported to down-regulate the MDR1 promoter in vitro. On the other hand, P-gp overexpression was hypothesized to contribute to Et-743 resistance in an ovarian cell line. The present study was performed to further investigate the relationship between P-gp/MDR1 and the activity of Et-743. First, we found no P-gp/MDR1 overexpression (mRNA and protein levels) in two independently generated Et-743-resistant human colon carcinoma cell lines (HCT116/ER5 and SW480/ER0.5). Secondly, we found no cross-resistance to Et-743 in two well-characterized P-gp/MDR1-overexpressing cell lines (KB-8-5 and KB-C-2). Third, Et-743 pretreatment enhanced the cytotoxicity and the cellular accumulation of doxorubicin and vincristine in P-gp/MDR1-overexpressing KB-8-5/KB-C-2 cell lines. Fourth, we observed P-gp/MDR1 down-regulation by Et-743 in KB-C-2 cells. These results indicate that Et-743 does not select for the emergence of a P-gp phenotype in all cell lines made resistant to Et-743 and that P-gp overexpression is not sufficient to confer resistance to Et-743. Furthermore, Et-743 is an effective agent in P-gp-overexpressing cells. Et-743 can potentiate the activity of other chemotherapeutic agents by down-regulating P-gp/MDR1, suggesting that the combination of Et-743 and chemotherapeutic agents that are substrates for P-gp/MDR1 may be valuable in the clinic.

Original languageEnglish
Pages (from-to)1327-1334
Number of pages8
JournalMolecular Cancer Therapeutics
Volume1
Issue number14
Publication statusPublished - 2002 Dec 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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