Ligustrazine derivate DLJ14 reduces multidrug resistance of K562/A02 cells by modulating GSTπ activity
Yu-Ning Song1, Xiu-Li Guo, Bei-Bei Zheng
1Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China.
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.
Insights
This study shows DLJ14, a ligustrazine derivative, can reverse multidrug resistance (MDR) in cancer cells. DLJ14 increases adriamycin (Adr) accumulation by inhibiting glutathione S-transferase π (GSTπ), enhancing chemotherapy effectiveness.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Multidrug resistance (MDR) in tumor cells is a significant challenge in cancer chemotherapy.
- Overexpression of glutathione S-transferase π (GSTπ) is a key mechanism contributing to MDR.
Purpose of the Study:
- To investigate the potential of DLJ14, a ligustrazine derivative, in reversing adriamycin (Adr) resistance in human myelogenous leukemia (K562/A02) cells.
- To explore DLJ14's effect on GSTπ expression and GST-related enzyme activity in MDR cancer cells.
Main Methods:
- Cell proliferation assessed using MTT assay.
- Adriamycin (Adr) accumulation measured in K562/A02 cells treated with DLJ14.
- Protein and mRNA expression of GSTπ analyzed via Western blot and RT-PCR.
- Expression of c-Jun NH(2)-terminal kinase (JNK) evaluated.
Main Results:
- DLJ14 enhanced the sensitivity of K562/A02 cells to adriamycin (Adr).
- DLJ14 increased intracellular Adr accumulation, potentially by downregulating GST-related enzyme activity.
- DLJ14 significantly inhibited both protein and mRNA expression of GSTπ.
- DLJ14 treatment led to increased cellular JNK expression in Adr-exposed K562/A02 cells.
Conclusions:
- DLJ14 demonstrates potential in reversing MDR by inhibiting GSTπ expression and activity.
- DLJ14 may serve as a valuable agent for enhancing the efficacy of cancer chemotherapy.
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