title: Ligustrazine derivate DLJ14 reduces multidrug resistance of K562/A02 cells by modulating GSTπ activity.
abstract: Multidrug resistance (MDR) of tumor cells is a major obstacle in chemotherapeutic cancer treatment. Over-expression of glutathione S-transferase π (GSTπ) is one of the mechanisms contributing to MDR. In this study, we investigated the reversal of MDR by DLJ14, a ligustrazine derivate, in adriamycin (Adr) resistant human myelogenous leukemia (K562/A02) cells by modulating the expression of GSTπ and the activity of GST-related enzymes. In the MTT test, DLJ14 showed a weak inhibition on proliferation of both K562/A02 and K562 cells, while verapamil at the same concentration showed a much stronger inhibition. The sensitivity of K562/A02 cells to cytotoxic killing by Adr was enhanced by incubation with DLJ14 as a result of the increased intracellular accumulation of Adr. The accumulation of Adr induced by DLJ14 may due to down regulation of GST-related enzyme activity. Western blot analysis and RT-PCR showed that DLJ14 was able to inhibit the protein expression and mRNA expression of GSTπ in K562/A02 cells. Moreover, DLJ14 increased the expression of cellular c-Jun NH(2)-terminal kinase (JNK) in K562/A02 cells exposure to Adr. This is consistent with the inhibition of GSTπ. These results demonstrate that DLJ14 may be an attractive new agent for the chemosensitization of cancer cells.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Song
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Guo
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Zheng
authors.forename: Xin-Yong
authors.initials: XY
authors.lastname: Liu
authors.forename: Xue
authors.initials: X
authors.lastname: Dong
authors.forename: Lu-Gang
authors.initials: LG
authors.lastname: Yu
authors.forename: Yan-Na
authors.initials: YN
authors.lastname: Cheng
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D051549:Glutathione S-Transferase pi / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; C560357:DLJ14 compound; D011719:Pyrazines; D012333:RNA, Messenger; D004317:Doxorubicin; D014700:Verapamil; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi