Scutellarin Increases Cisplatin-Induced Apoptosis and Autophagy to Overcome Cisplatin Resistance in Non-small Cell Lung Cancer via ERK/p53 and c-met/AKT Signaling Pathways

Abstract

Cisplatin, as the first-line anti-tumor agent, is widely used for treatment of a variety of malignancies including non-small cell lung cancer (NSCLC). However, the acquired resistance has been a major obstacle for the clinical application. Scutellarin is a active flavone extracted from Erigeron breviscapus Hand-Mazz that has been shown to exhibit anticancer activities on various types of tumors. Here, we reported that scutellarin was capable of sensitizing A549/DDP cells to cisplatin by enhancing apoptosis and autophagy. Mechanistic analyses indicated that cisplatin-induced caspase-3-dependent apoptosis was elevated in the presence of scutellarin through activating extracellular signal-regulated kinases (ERK)-mediated p53 pathway. Furthermore, scutellarin also promoted cisplatin-induced cytotoxic autophagy, downregulated expression of p-AKT and c-met. Deficiency of c-met reduced p-AKT level, and inhibition of p-AKT or c-met improved autophagy in A549/DDP cells. Interestingly, loss of autophagy attenuated the synergism of this combination. In vivo, the co-treatment of cisplatin and scutellarin notably reduced the tumor size when compared with cisplatin treatment alone. Notably, scutellarin significantly reduced the toxicity generated by cisplatin in tumor-bearing mice. This study identifies the unique role of scutellarin in reversing cisplatin resistance through apoptosis and autophagy, and suggests that combined cisplatin and scutellarin might be a novel therapeutic strategy for patients with NSCLC.

The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin

“…Many previous studies mainly focused on reactivating pro-apoptotic signals to enhance cell sensitivity to cisplatin (Rudin et al, 2003;Weir et al, 2007;Sun et al, 2018). The present study mimicked the generating process of cell resistance to cisplatin in vitro.…”

“…However, studies have shown that despite DNA damage, the signals promoting cell death are not sufficiently activated, which is partly due to mutations or downregulation of signaling molecules that drive cell death and also due to upregulation of signaling molecules preventing cell death. Many previous studies mainly focused on reactivating pro-apoptotic signals to enhance cell sensitivity to cisplatin (Rudin et al, 2003;Weir et al, 2007;Sun et al, 2018). Although some improvements of cell sensitivity to anti-cancer drugs have been made by promoting apoptosis, many cancer cells still show strong resistance to anti-cancer drugs through some undefined mechanisms, especially in clinical settings.…”

Scutellarin suppresses proliferation and promotes apoptosis in A549 lung adenocarcinoma cells via AKT/mTOR/4EBP1 and STAT3 pathways

“…Sun et al . reported that SCU enhanced cisplatin‐induces apoptosis and autophagy via the extracellular signal‐regulated kinase (ERK)/P53 or c‐met/AKT signaling pathways . This group also revealed that SCU induces apoptosis and autophagy in NSCLC cells through ERK1/2 and AKT signaling pathways in vitro and in vivo .…”

“…20,21 Sun et al reported that SCU enhanced cisplatin-induces apoptosis and autophagy via the extracellular signal-regulated kinase (ERK)/P53 or c-met/AKT signaling pathways. 22 This group also revealed that SCU induces apoptosis and autophagy in NSCLC cells through ERK1/2 and AKT signaling pathways in vitro and in vivo. 23 Deng et al showed that SCU inhibits human renal cancer cell proliferation and migration via upregulation of phosphatase and tensin homolog, 24 while Ke et al reported that SCU effectively inhibits hepatocellular carcinoma metastasis in vivo and the migration and invasion of hepatocellular carcinoma cells in vitro.…”

Oleandrin synergizes with cisplatin in human osteosarcoma cells by enhancing cell apoptosis through activation of the p38 MAPK signaling pathway

“…DDP exerts cytotoxicity mainly by triggering cell apoptosis [ 20 ]. In embryonal carcinoma and lung cancer, drugs sensitize tumor cells to DDP by enhancing DDP-induced apoptosis [ 21 , 22 ]. Two main apoptotic pathways are involved in the cytotoxic agents-mediated apoptosis: the intrinsic and extrinsic pathways.…”