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

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.

Pharmacological Inhibition of p38 MAPK by SB203580 Increases Resistance to Carboplatin in A2780cp Cells and Promotes Growth in Primary Ovarian Cancer Cells

“…These studies indicate that survivin is involved in multiple biological processes in EOC. Previous studies have shown that p38 MAPK is required for survivin downregulation in Tanshinone IIA and a high dose of nitric oxide-induced apoptosis in established EOC cell lines [21,35,36]. Our results show that inhibition of p38 MAPK by SB203580 increases survivin protein level in the primary EOC cells, which is consistent with the published results in established EOC cell lines [21,35,36].…”

“…Survivin is implicated in cisplatin-induced cytotoxicity in EOC [33,34]. Because published studies showed that p38 MAPK mediates survivin downregulation and apoptosis induced by tanshinone IIA and a high dose of nitric oxide in EOC cells [21,35,36], we examined how carboplatin and SB203580 treatment affects survivin expression in the primary EOC cells. Western blotting showed that SB203580 increased the expression of survivin in all primary EOC cells compared to the DMSO control, albeit to a variable extent (Figure 5).…”

“…Thus far, studies carried out in established EOC cell lines have reported contradictory results regarding the role of p38 MAPK in cisplatin resistance in EOC. While most studies showed that activation of p38 MAPK contributes to cytotoxicity in EOC cells [15,16,17,18,19,20,21,22,23,24], one recent study reported that inhibition of p38 MAPK sensitizes EOC cells to cisplatin [25]. In this study, we found that activation of p38 MAPK is dispensable for carboplatin-induced cell death in cisplatin-sensitive A2780s cells, but it is partially required for carboplatin-induced cell death in cisplatin-resistant A2780cp cells.…”

“…Previous studies have shown that p38 MAPK is required for survivin downregulation in Tanshinone IIA and a high dose of nitric oxide-induced apoptosis in established EOC cell lines [21,35,36]. Our results show that inhibition of p38 MAPK by SB203580 increases survivin protein level in the primary EOC cells, which is consistent with the published results in established EOC cell lines [21,35,36]. However, further experiments are required to determine whether increased survivin contributes to SB203580-mediated increases in viable cells in the primary EOC cells.…”

“…In terms of platinum resistance in EOC, most studies used established EOC cell lines and determined that activation of p38 MAPK is pro-apoptotic in cisplatin-induced cytotoxicity in EOC cells [15,16,17,18,19]. Additionally, activation of p38 MAPK has been shown to be involved in apoptosis induced by several other antitumor agents in cisplatin-resistant EOC cells [20,21,22,23,24]. On the other hand, one recent study showed that activation of p38 MAPK contributes cisplatin resistance in EOC cells [25].…”