Arteannuin B Enhances the Effectiveness of Cisplatin in Non-Small Cell Lung Cancer by Regulating Connexin 43 and MAPK Pathway

Abstract

Cisplatin (DDP)-based chemotherapy is the first-line regimen for advanced non-small cell lung cancer (NSCLC) patients. However, advanced NSCLC patients may have innate resistance to DDP or develop resistance during DDP treatment. We investigated a natural compound, arteannuin B (Art B), for its potential effects on DDP resistance in NSCLC. Art B was isolated from Artemisia annua by chromatographic purification and spectral elucidation. The activities of Art B on DDP-mediated effects were examined using in vitro and in vivo assays. We observed significant correlations in T stage, clinical stage, chemotherapy resistance and poor survival of NSCLC patients with low Cx43 expression. Art B enhanced the effectiveness of cisplatin by increasing Cx43 expression in normal and DDP-resistant NSCLC cells. Art B also increased DDP uptake through up-regulating Cx43. The combination of DDP and Art B showed better therapeutic effect than individual treatments both in vitro and in vivo. Art B increased intracellular Fe[Formula: see text] level, promoted calcium influx, and activated gap junction and MAPK pathways, which might contribute to Art B-mediated effects. Art B may serve as a new drug candidate to enhance the antitumor effect of DDP on NSCLC.

ITGB3 promotes cisplatin resistance in osteosarcoma tumors

“…It is interesting to note that KEGG pathway enrichment was observed only in the downregulated group (Figure 5F ; Table S3 ). Among these enrichments, some signaling pathways were commonly related to cisplatin resistance in osteosarcomas, such as the mitogen‐activated protein kinase (MAPK) pathway 20 , 21 , 22 , 23 , 24 and vascular endothelial growth factor (VEGF). 25 , 26 , 27 Additionally, 10 hub genes were identified, and their associated signaling pathways were demonstrated (Figure 5G ).…”

Meta‐analysis of microarray data to determine gene indicators involved in cisplatin resistance in non‐small cell lung cancer

“…Huang et al have reported a novel adjuvant compound, arteannuin B (Art B), that enhances the cytotoxicity of cisplatin by facilitating its uptake into the cancer cells. This is mediated by the upregulation of connexin43, the activation of gap junction and MAPK pathways, and the increase of intracellular Fe2+ and calcium influx 29 …”

“…Consistent with our hypothesis, a recent study has interestingly highlighted the importance of gap junction activation and MAPK pathways for overcoming cisplatin resistance in NSCLC. 29 Huang et al…”

“…This is mediated by the upregulation of connexin43, the activation of gap junction and MAPK pathways, and the increase of intracellular Fe2+ and calcium influx. 29 DNA damage, a common feature of many anticancer drugs, leads to genome instability and cell death in cancer cells treated with cisplatin. The base excision repair (BER) pathway modulates the Consistent with these data, the downregulation of NTHL1 and SMUG1…”

“…Consistent with our hypothesis, a recent study has interestingly highlighted the importance of gap junction activation and MAPK pathways for overcoming cisplatin resistance in NSCLC. 29 Huang et al have reported a novel adjuvant compound, arteannuin B (Art B), that enhances the cytotoxicity of cisplatin by facilitating its uptake into the cancer cells. This is mediated by the upregulation of connexin43, the activation of gap junction and MAPK pathways, and the increase of intracellular Fe2+ and calcium influx.…”