Reversal effect of a macrocyclic bisbibenzyl plagiochin E on multidrug resistance in adriamycin-resistant K562/A02 cells

• Published in: European journal of pharmacology 2008-04, Vol.584 (1), p.66-71
• Main Authors: Shi, Yan-qiu, Qu, Xian-jun, Liao, Yong-xiang, Xie, Chun-feng, Cheng, Yan-na, Li, Song, Lou, Hong-xiang
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Apoptosis - drug effects; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Bridged-Ring Compounds - pharmacology; Bridged-Ring Compounds - therapeutic use; Cell Proliferation - drug effects; Cell Separation; Cell Survival - drug effects; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin - metabolism; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Interactions; Drug Resistance, Neoplasm - drug effects; Flow Cytometry; Humans; K562 Cells; K562/A02 cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Medical sciences; Multidrug resistance; P-glycoprotein; Pharmacology. Drug treatments; Plagiochin E; Reversal; Rhodamine 123 - metabolism; Stilbenes - pharmacology; Stilbenes - therapeutic use; Time Factors
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2008.01.039

Plagiochin E is a new macrocyclic bisbibenzyl compound isolated from Marchantia polymorpha. In the previous studies, we reported that when combined with fluconazole, plagiochin E had synergetic effects against the resistant strain of Candida albicans. Herein, we examined the reversal effect of plagiochin E on multidrug resistance in adriamycin-induced resistant K562/A02 cells and the parental K562 cells. Its cytotoxicity and reversal effects on multidrug resistance were assessed by MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide) assay. Apoptosis percentage of cells was obtained from Annexin V/fluorescein isothiocyanate (FITC) and propridium iodide (PI) double-staining. The effects of plagiochin E on P-glycoprotein activity were evaluated by measuring rhodamine 123 (Rh123)-associated mean fluorescence intensity and P-glycoprotein expression on the basis of the flow cytometric technology, respectively. The results showed that plagiochin E ranging from 2 to 12 μg/ml had little cytotoxicity against K562/A02 cells. When combined with adriamycin, it significantly promoted the sensitivity of K562/A02 cells toward adriamycin through increasing intracellular accumulation of adriamycin in a dose-dependent manner. Further study demonstrated that the inhibitory effect of plagiochin E on P-glycoprotein activity was the major cause of increased stagnation of adriamycin inside K562/A02 cells, indicating that plagiochin E, as a new class of mutidrug resistance inhibitor, may effectively reverse the multidrug resistance in K562/A02 cells via inhibiting expression and drug-transport function of P-glycoprotein.