Human multidrug resistance associated protein 4 resitance to camtothecins

Tian, Quan, Zhang, Jing, Tan, Theresa May Chin, Chan, Eli, Duan, Wei, Chan, Sui Yung, Boelsterli, Urs Alex, Ho, Paul Chi-Lui, Yang, Hongyuan, Bian, Jin-Song, Huang, Min, Zhu, Yi-Zhun, Xiong, Weiping, Li, Xiaotian and Zhou, Shufeng 2005, Human multidrug resistance associated protein 4 resitance to camtothecins, Pharmaceutical research, vol. 22, no. 11, pp. 1837-1853.

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Title Human multidrug resistance associated protein 4 resitance to camtothecins
Author(s) Tian, Quan
Zhang, Jing
Tan, Theresa May Chin
Chan, Eli
Duan, Wei
Chan, Sui Yung
Boelsterli, Urs Alex
Ho, Paul Chi-Lui
Yang, Hongyuan
Bian, Jin-Song
Huang, Min
Zhu, Yi-Zhun
Xiong, Weiping
Li, Xiaotian
Zhou, Shufeng
Journal name Pharmaceutical research
Volume number 22
Issue number 11
Start page 1837
End page 1853
Publisher Springer
Place of publication New York, N.Y.
Publication date 2005-11
ISSN 0724-8741
1573-904X
Keyword(s) camptothecin
cyclophosphamide
drug transporter
multidrug resistance
Summary Purpose The multidrug resistance associated protein (MRP) 4 is a member of the adenosine triphosphate (ATP)-binding cassette transporter family. Camptothecins (CPTs) have shown substantial anticancer activity against a broad spectrum of tumors by inhibiting DNA topoisomerase I, but tumor resistance is one of the major reasons for therapeutic failure. P-glycoprotein, breast cancer resistance protein, MRP1, and MRP2 have been implicated in resistance to various CPTs including CPT-11 (irinotecan), SN-38 (the active metabolite of CPT-11), and topotecan. In this study, we explored the resistance profiles and intracellular accumulation of a panel of CPTs including CPT, CPT-11, SN-38, rubitecan, and 10-hydroxy-CPT (10-OH-CPT) in HepG2 cells with stably overexpressed human MRP4. Other anticancer agents such as paclitaxel, cyclophosphamide, and carboplatin were also included.
Methods HepG2 cells were transfected with an empty vehicle plasmid (V/HepG2) or human MRP4 (MRP4/HepG2). The resistance profiles of test drugs in exponentially growing V/HepG2 and MRP4/HepG2 cells were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay with 4 or 48 h exposure time of the test drug in the absence or presence of various MRP4 inhibitors. The accumulation of CPT-11, SN-38, and paclitaxel by V/HepG2 and MRP4/HepG2 cells was determined by validated high-performance liquid chromatography methods.
Results Based on the resistance folds from the MTT assay with 48 h exposure time of the test drug, MRP4 conferred resistance to CPTs tested in the order 10-OH-CPT (14.21) > SN-38 carboxylate (9.70) > rubitecan (9.06) > SN-38 lactone (8.91) > CPT lactone (7.33) > CPT-11 lactone (5.64) > CPT carboxylate (4.30) > CPT-11 carboxylate (2.68). Overall, overexpression of MRP4 increased the IC50 values 1.78- to 14.21-fold for various CPTs in lactone or carboxylate form. The resistance of MRP4 to various CPTs tested was significantly reversed in the presence of dl-buthionine-(S,R)-sulfoximine (BSO, a γ-glutamylcysteine synthetase inhibitor), MK571, celecoxib, or diclofenac (all MRP4 inhibitors). In addition, the accumulation of CPT-11 and SN-38 over 120 min in MRP4/HepG2 cells was significantly reduced compared to V/HepG2 cells, whereas the addition of celecoxib, MK571, or BSO significantly increased their accumulation in MRP4/HepG2 cells. There was no significant difference in the intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells, indicating that P-glycoprotein was not involved in the observed resistance to CPTs in this study. MRP4 also conferred resistance to cyclophosphamide and this was partially reversed by BSO. However, MRP4 did not increase resistance to paclitaxel, carboplatin, etoposide (VP-16), 5-fluorouracil, and cyclosporine.
Conclusions Human MRP4 rendered significant resistance to cyclophosphamide, CPT, CPT-11, SN-38, rubitecan, and 10-OH-CPT. CPT-11 and SN-38 are substrates for MRP4. Further studies are needed to explore the role of MRP4 in resistance, toxicity, and pharmacokinetics of CPTs and cyclophosphamide.

Language eng
Field of Research 111502 Clinical Pharmacology and Therapeutics
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2005, Springer Science + Business Media, Inc.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30009167

Document type: Journal Article
Collection: School of Medicine
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