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›› 2004, Vol. 21 ›› Issue (4): 549-556.DOI: 10.7523/j.issn.2095-6134.2004.4.019

• Excerpt of Dissertation • Previous Articles     Next Articles

Exploration on Anti-Multidrug-Resistant Molecular Mechanisms of Salvicine and Characterization of Salvicine-Resistant A549/SAL Cell Line

MIAO Ze-Hong, DING Jian   

  1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China
  • Received:2004-03-17 Online:2004-07-10
  • Supported by:

    the National Natural Science Foundation of China(30070877,30330670,30228032);Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2SW202) and the High Tech Research and Development(863)Program of the Ministry of Scienceand Technology

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

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