Abstract:

Multidrug resistance (MDR) is a major clinical problem in treating human cancers withconventional chemotherapeutic drugs. This study demonstrated that salvicine, a novel antitumor compoundunder clinical trial, exerted direct cytotoxicity against MDR tumor cells and down-regulated mdr-1 PP-glycoprotein (Pgp) expression simultaneously. Salvicine effectively killed MDR sublines, such as K562/A02, KBPVCR and MCF-7PADR, and parental K562, KB, and MCF-7 cell lines to an equivalentdegree. Its cytotoxic activities were much more potent than those of several classical anticancer drugs.Salvicine induced the downregulation of mdr-1 gene and P-gp expression, while not affecting MRP andLRP expression. Anti-MDR mechanism exploration revealed that transcription factor c-Jun played aprincipal role in downregulation of mdr-1 expression and induction of apoptosis by salvicine. Levels of c-jun expression were enhanced by salvicine prior to reduction of mdr-1 expression in K562/A02 cells.Moreover, c-jun antisense oligodeoxynucleotides (AODs) prevented salvicine-stimulated enhancement of c-Jun protein and reduction of mdr-1 gene expression, but did not affect the increase in c-jun mRNAlevels. Salvicine promoted phosphorylation of JNK kinase and c-Jun protein and enhanced DNA bindingactivity of transcription factor AP1. Additionally, c-jun AODs also inhibited salvicine-induced apoptosisand cytotoxicity. Finally, salvicine was further shown not to induce a tumor MDR phenotype. Weestablished a salvicine-resistant tumor cell subline, A549/SAL, which displayed 8.91-fold resistance tosalvicine and an average of 61702fold resistance to the antimetabolites. The subline, however, was notresistant to alkylating agents, platinum compounds, and other naturally-derived antineoplastics

Key words: salvicine, multidrug resistance, mdr21, c2jun, A549PSAL cells