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.