Objectives: We investigated the chemo-sensitization of a ligustrazine derivate, (E)-2-(2, 4-dimethoxystyryl)-3, 5, 6-trimethylpyrazine (DLJ14) on Adriamycin (Adr, Wanle, Shenzhen, China)-resistant human breast cancer (MCF-7/A) cells both in vivo and in vitro.
Methods: The antitumour effects of DLJ14 and Adr was observed in MCF-7/A cells by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro and was evaluated by MCF-7/A xenografts in nude mice. The intracellular Adr accumulation was assessed by mean fluorescence intensity of Adr. The messenger RNA level of glutathione (GSH) S-transferase (GST)π in MCF-7/A cells was determined by real-time reverse transcription PCR assay. The expression of GSTπ, c-jun NH2 -terminal kinase (JNK) and phosphor-JNK (p-JNK) was detected by Western blotting method.
Key findings: The MTT results showed that DLJ14 exhibited a weak inhibition on proliferation of both MCF-7 and MCF-7/A cells, in contrast with the strong inhibition of verapamil. When DLJ14 is combined with Adr, the inhibitory effect on MCF-7/A cells and MCF-7/A xenografts was enhanced significantly through increasing intracellular accumulation of Adr by inhibition of GSH level and the activity of GSH peroxidase and GST. Moreover, DLJ14 could downregulate the expression of GSTπ and increase the expression of JNK and p-JNK in MCF-7/A cells or in xenografts.
Conclusion: DLJ14 is a promising chemo-sensitization candidate for the reversal of multidrug resistance in cancers.
Keywords: (E)-2-(2,4-dimethoxystyryl)-3,5,6-trimethylpyrazine (DLJ14); Adr-resistant human breast cancer cell (MCF-7/A cell); glutathione S-transferase π (GSTπ); multiple drug resistance; tumour xenograft.
© 2013 Royal Pharmaceutical Society.