Overcoming multidrug drug resistance in P-glycoprotein/MDR1-overexpressing cell lines by ecteinascidin 743.
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.
Kanzaki
Atsuko
A
Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
Takebayashi
Yuji
Y
Ren
Xiao-Qin
XQ
Miyashita
Hitoshi
H
Mori
Shiro
S
Akiyama
Shin-ichi
S
Pommier
Yves
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000494:pharmacology*; D008956:Models, Chemical; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044005:Tetrahydroisoquinolines; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D000077606:Trabectedin; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D014750:Vincristine; D004317:Doxorubicin; C022616:thiazolyl blue; D000077606:Trabectedin