title: Tanshinone IIA acts via p38 MAPK to induce apoptosis and the down-regulation of ERCC1 and lung-resistance protein in cisplatin-resistant ovarian cancer cells.
abstract: Tanshinone IIA is known to induce apoptosis in several types of cancer cells. However, little is known about its activity in chemoresistant cells. The aim of this study was to investigate the anticancer properties of tanshinone IIA in cisplatin-resistant human ovarian cancer COC1/DDP cells in vitro. We used a variety of methods to measure cell viability, the resistance index (RI) of cisplatin, cellular apoptosis, p38 mitogen-activated protein kinase (MAPK) expression and phosphorylation, and the mRNA expression of several genes implicated in drug resistance including survivin, Caspase-3, excision repair cross-complementing gene 1 (ERCC1), multidrug resistance (MDR), lung resistance protein (LRP) and glutathione-S-transferase-π (GST-π). We found that tanshinone IIA time- and dose-dependently inhibited the proliferation of COC1/DDP cells and caused significant apoptosis. Western blotting revealed that tanshinone IIA also increased phospho-p38 MAPK in a time- and dose-dependent manner. After treatment by tanshinone IIA for 48 h, the RI of cisplatin and the mRNA expression of survivin, ERCC1 and LRP were all significantly decreased. Furthermore, blockade of p38 signal transduction decreased apoptotic cell rates and dramatically elevated the mRNA expression of the survivin, ERCC1 and LRP genes. We therefore conclude that tanshinone IIA induces apoptosis and reduces cisplatin resistance in COC1/DDP cells and thus causes significant growth inhibitory effects. This mechanism appears to involve p38-mediated downregulation of survivin, ERCC1 and LRP mRNA expression.
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, PR China.
authors.forename: Jin-Wen
authors.initials: JW
authors.lastname: Jiao
authors.forename: Fang
authors.initials: F
authors.lastname: Wen
mesh_terms: D045784:Abietanes / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D000099187:Major Vault Protein
chemical_list: D045784:Abietanes; D000970:Antineoplastic Agents; D002945:Cisplatin; D004268:DNA-Binding Proteins; D004720:Endonucleases; D020394:Vault Ribonucleoprotein Particles; D048051:p38 Mitogen-Activated Protein Kinases; D000099187:Major Vault Protein; C021751:tanshinone; C071447:ERCC1 protein, human