Isoquercitrin inhibits the progression of pancreatic cancer in vivo and in vitro by regulating opioid receptors and the mitogen-activated protein kinase signalling pathway

Abstract

Pancreatic cancer is a common malignant tumour that affects individuals worldwide. In recent years, the incidence and mortality rates of pancreatic cancer have continuously increased. Currently, the primary clinical treatment methods for pancreatic cancer include surgical resection, chemotherapy and radiotherapy. However, these treatment methods rarely produce satisfactory therapeutic outcomes. Extensive research has also proven that the effective components of several traditional Chinese medicines, particularly flavonoids extracted from plants, have significant antitumour effects. Isoquercitrin, which is one of the flavonoids found in Bidens pilosa extracts, has a significant antitumour effect. However, the antitumour effect of isoquercitrin and its mechanism of action remain unclear. The objective of the present study was to investigate the effect of isoquercitrin on the progression of pancreatic cancer and to further understand the biological characteristics of the participation of isoquercitrin in the progression of pancreatic cancer. In vitro, we found that a therapeutic dose of isoquercitrin significantly inhibited proliferation, promoted apoptosis and induced cell cycle arrest within the G1 phase in pancreatic cancer cells. Isoquercitrin activated caspase-3, -8 and -9 and reduced the mitochondrial membrane potential. In addition, isoquercitrin inhibited the expression level of the δ opioid receptor; however, isoquercitrin had no effect on the κ and µ opioid receptors. Furthermore, isoquercitrin inhibited extracellular signal-regulated kinase (ERK) phosphorylation and promoted c-Jun N-terminal kinase (JNK) phosphorylation. In vivo, we found that a therapeutic dose of isoquercitrin significantly inhibited xenograft growth in nude mice. In summary, the present study demonstrated that isoquercitrin inhibits human pancreatic cancer progression in vivo and in vitro and that its molecular mechanism may be closely related to opioid receptors and to the activation of the mitogen-activated protein kinase (MAPK) signalling pathway.

Review of anticancer mechanisms of isoquercitin

“…It described new Wnt pathway regulation mechanisms, which may be responsible for the induction of colorectal cancer invasion related to MLK3 mutations. A reasonable hypothesis for the IQ antitumor mechanism would be the involvement of signaling pathways mediat ing its modulation of Wnt signaling [74] , which would reaffirm data presented by other studies [67,77] . The Wnt pathway in turn, is related to the p53 pathway (via apoptosis), and published literature has demonstrated its mediation of the apoptosisinducing action of IQ [73] .…”

“…Furthermore, IQ inhibited the phosphorylation of extracellular signalregulated kinase (ERK) and promoted the phosphorylation of cJun Nterminal kinase (JuNK). In vivo, IQ inhibited xenograft growth in nude mice [74] .…”

“…The Wnt pathway in turn, is related to the p53 pathway (via apoptosis), and published literature has demonstrated its mediation of the apoptosisinducing action of IQ [73] . The induction of apoptosis may be related to caspases, inhibition of ERK phosphorylation, and promotion of JuNK phosphorylation [74] . Another possibility with the apoptotic pathway would be an association with the GSTP(+) foci.…”

Isoquercitrin protects against pulmonary hypertension via inhibiting PASMCs proliferation

“…ERK1/2 phosphorylation was increased by PDGF‐BB in this study and IQC attenuated PDGF‐BB‐stimulated phosphorylation of these proteins. The same results were reported by Chen in the study of pancreatic cancer that IQC inhibited the progression of pancreatic cancer in vivo and in vitro by regulating the ERK1/2 signalling pathway . Therefore, these findings indicated that ERK1/2 likely synergized with Akt/GSK3β signalling pathway to regulate PASMCs proliferation.…”

“…The same results were reported by Chen in the study of pancreatic cancer that IQC inhibited the progression of pancreatic cancer in vivo and in vitro by regulating the ERK1/2 signalling pathway. 33 Therefore, these findings indicated that ERK1/2 likely synergized with Akt/GSK3β signalling pathway to regulate PASMCs proliferation. In summary, the present study showed that IQC alleviated the process of PAH through inhibiting PASMCs proliferation and pulmonary vascular remodelling.…”