| Gastric cancer is one of the most common malignancies in the world.The main treatment of advanced gastric cancer has still been the chemotherapy,however,often in the course of treatment will produce resistance.It has been reported that the diterpenoid product Tanshinones isolated from the Chinese traditional medicinal Salvia miltiorrhiza exhibits various anticancer activities,and in particular,it can reverse cancer cell resistance in different cancers.Therefore,the purpose of this study was to investigate whether Tanshinone ?A(TAN ?A),the highest active ingredient in Salvia miltiorrhiza plant,could reverse the drug resistance of gastric cancer cells to a broad spectrum anti-cancer drug,Doxorubicin(DOX).Objective: To investigate whether TAN ?A can reverse the drug resistance of DOX-resistant gastric cancer cells and explore its underlying molecular mechanism..Methods: Based on the IC50 of DOX,SNU-719 and SNU-610,which are sensitive to DOX,and gastric cancer cells SNU-638,SNU-668,SNU-216 and SNU-620 Drug resistance of DOX-resistant gastric cancer cell lines SNU-719 R and SNU-610 were established by stepwise increase of selective drug concentration.Two kinds of DOX-sensitive gastric cancer cells SNU-719 and SNU-610 were selected as the parental cells.610R(acquired drug resistance);DOX and DOX + TAN ?A treatment of two different ways,by flow cytometry analysis of cell cycle distribution,apoptosis and drug efflux;combined with Real-time PCR detection of related drugs Efflux transporter m RNA expression;the use of Western blot analysis of various cell-related protein expression levels;by ELISA to determine apoptosis-related protease activity.Results:(1)TAN ?A can reverse the drug resistance of DOX-induced gastric cancer cells after combined administration of TAN ?A and DOX.(2)In the case of multidrug resistance-associated protein 1(MRP1)overexpression,DOX resistance,the combination of TAN ?A and DOX can cause down-regulation of MRP1 and reverse the resistance of DOX to gastric cancer cells;(3)The presence of TAN ?A can cause cell cycle G2 / M arrest in DOX-resistant gastric cancer cells Hysteresis;(4)TAN ?A co-treated with DOX cells,we tested the pro-apoptotic protein p53 and Bax upregulation,anti-apoptotic protein Bcl-2 down regulation,accompanied by flow cytometry analysis of different drugs Apoptosis proved that TAN ?A could induce the increase of apoptosis in gastric cancer drug-resistant cells;(5)Co-treatment with DOX and TAN ?A caused a significant upregulation of autophagy-related protein LC3B-? in gastric cancer cells and p62 down,indicating that TAN ?A can activate autophagy signaling,induction of gastric cancer drug-resistant cell autophagic cell death,and ultimately achieve the purpose of reversal of drug resistance.Conclusion: TAN ?A can reverse the drug resistance of DOX-resistant gastric cancer cells and is a potential agent that can participate in the treatment of gastric cancer combined with drug therapy. |
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