Triptolide avoids cisplatin resistance and induces apoptosis via the reactive oxygen species/nuclear factor-κB pathway in SKOV3PT platinum-resistant human ovarian cancer cells

Abstract

An acquired resistance to platinum-based drugs has emerged as a significant impediment to effective ovarian cancer therapy. The present study explored the anticancer mechanisms of triptolide (TPL) in SKOV3PT platinum-resistant human ovarian cancer cells and observed that TPL activated caspase 3 and induced the dose-dependent apoptosis of the SKOV3PT cells. Furthermore, TPL inhibited complex I of the mitochondrial respiratory chain (MRC) followed by an increase of reactive oxygen species (ROS), which further inhibited nuclear factor (NF)-κB activation and resulted in the downregulation of anti-apoptotic proteins, Bcl-2 and X-linked inhibitor of apoptosis protein (XIAP). Notably, the pre-treatment with N-acetyl-L-cysteine (NAC) abolished the TPL-induced ROS generation, NF-κB inhibition and cell apoptosis, but did not affect the inhibitory effect of TPL on complex I activity. These results suggested that TPL negatively regulated the NF-κB pathway through mitochondria-derived ROS accumulation, promoting the apoptosis of the SKOV3PT cells. Furthermore, TPL synergistically enhanced the cytotoxicity of cisplatin against platinum-resistant ovarian cancer cells. Collectively, these findings suggest that TPL is able to overcome chemoresistance and that it may be an effective treatment for platinum-resistant ovarian cancer, either alone or as an adjuvant therapy.

Synergistic Antitumor Effect of Triptolide and Cisplatin in Cisplatin Resistant Human Bladder Cancer Cells

“…20 In various experimental models several studies demonstrated the synergistic anticancer effect of TPL combined with select anticancer agents such as cisplatin and oxaliplatin. 21,22 However, to our knowledge ours is the first study to show that TPL synergistically enhances the antitumor effects of cisplatin and resensitizes cisplatin resistant human bladder cancer cells.…”

“…These results are in agreement with those of previous studies demonstrating that TPL could sensitize platinum resistant SKOV3 PT cells to cisplatin by inducing apoptosis. 21 Li and Hu also reported that the combination of TPL plus cisplatin reduced cell viability and enhanced apoptosis with a single treatment in liver cancer cells. 28 In addition, endogenous prosurvival molecules, including the antiapoptotic Bcl-2 family, serinethreonine kinase Akt and the Ras/Raf/MEK/Erk pathway, inhibit apoptosis.…”

IL-17A exacerbates cisplatin-based resistance of OVCA via upregulating the expression of ABCG2 and MDR1 through Gli1-mediated Hh signaling

“…Increasing evidences showed that the up-regulating of ABC proteins such as ABCG2 and MDR1 are involved in cisplatin-induced resistance [41,42]. Literatures also reported that DDP exerts cytotoxicity via inducing apoptosis [33,34]. Therefore, we hypothesis that IL-17A may impact drug resistance of OVCA by up-regulating the levels of MDR1 and ABCG2.…”

“…The literatures report that DDP exerts cytotoxicity via inducing apoptosis [33,34]. To determine whether the increased DDP-resistance by rhIL-17A is correlated with apoptosis, the A2780 and OVCAR3 cells were treated with rhIL-17A, DDP, or DDP along with rhIL-17A for 24h and then were analyzed by flow cytometry (Figure 3).…”

Upregulation of Death Receptor 5 and Production of Reactive Oxygen Species Mediate Sensitization of PC-3 Prostate Cancer Cells to TRAIL Induced Apoptosis by Vitisin A

“…It is well documented that ROS plays a critical role in apoptosis induction in several cancers [30][31][32][33] and also ROS mediates TRAIL sensitization through modulation of TRAIL receptor DR5 in prostate cancer cells by several cancer chemopreventive agents such as Orlistat [34], Celastraol [35] and Baicalein [36]. Our flow cytometric analysis revealed that combination of TRAIL and Vitisin A increased the production of ROS and conversely ROS inhibitor NAC blocked the ability of combination of TRAIL and Vitisin A to cleave PARP in PC-3 cells, indicating the role of ROS in apoptotic effect by combination of TRAIL and Vitisin A.…”