Salvicine is a diterpenoid quinone derived from a traditional Chinese medication that has been shown to possess potent in vitro and in vivo antitumor effects. This compound, which inhibits the activity of Topoisomerase II, was found to equipotently kill various multidrug-resistant tumor cells and their corresponding parental counterparts in vitro and to inhibit mdr1/P-gp expression in multidrug-resistant K562/A02 cells. To examine the features of tumor resistance to salvicine, we established a salvicine-resistant tumor cell subline of A549 lung adenocarcinoma cells. Compared with parental cells, A549/SAL cells displayed 8.91-fold resistance to salvicine and an average of 6.70-fold resistance to the antimetabolites. A549/SAL cells, however, were not resistant to alkylating agents, platinum compounds and other naturally-derived antineoplastics. RT-PCR analysis showed that the expression of mRNAs from the mdr-1, MRP, PCNA, topoisomerase II alpha and beta, GSTpi, p21 and GADD45 genes was not altered in the salvicine-resistant subline. In contrast, expression of p53 and bax mRNA was significantly lower, and expression of mdm2 mRNA was significantly higher, in A549/SAL cells compared to A549 cells. A549/SAL cells grew more slowly, and in a more scattered pattern, than A549 cells. In addition, the A549/SAL cells showed enhanced ability to migrate and invade in comparison to the parental cells. These results indicate that exposure to salvicine does not induce a tumor multidrug-resistant phenotype.
Copyright 2004 Wiley-Liss, Inc.