Paeoniflorin Potentiates the Inhibitory Effects of Erlotinib in Pancreatic Cancer Cell Lines by Reducing ErbB3 Phosphorylation

Abstract

Blockade of the epidermal growth factor receptor (EGFR) by EGFR tyrosine kinase inhibitors is insufficient for effective anti-tumor activity because the reactivation of the ErbB3 signaling pathway significantly contributes to activating the consequent phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Combinatorial therapies including ErbB3 targeting may ameliorate tumor responses to anti-EGFR therapies. In the present study, we found that in BxPC-3 and L3.6pl cells, which highly expressed the ErbB3 receptor, significant reduction in cell viability, induction of apoptosis were observed when treated with a combination of erlotinib and PF compared to either agent alone. Moreover, in ErbB3-expressing BxPC-3, L3.6pl and S2VP10 cell lines, the inhibition of ErbB3/PI3K/Akt phosphorylation were observed when treated with PF. Most strikingly, both EGFR/MAPK/Erk and ErbB3/PI3K/Akt activitions were substantially suppressed when treated with the combination of PF and erlotinib. However, in the ErbB3-deficient cell line MIAPaCa-2, no such effects were observed with similar treatments. Most importantly, these in vitro results were replicated in nude mouse transplanted tumor models. Taken together, our findings show that PF enhances the effect of erlotinib in ErbB3-expressing pancreatic cancer cells by directly suppressing ErbB3 activation, and PF in combination with erlotinib is much more effective as an antitumor agent compared with either agent alone.

Paeoniflorin: a monoterpene glycoside from plants of Paeoniaceae family with diverse anticancer activities

“…Based on studies performed in recent years, it is found Paeoniflorin combined with gemcitabine inhibits pathways EGFR/ MAPK/ERK and ErbB3/PI3K/Akt, and increases proliferation of pancreatic cancer cell ErbB3. [46] Some other studies show that Paeoniflorin in concentration of 1000 lmol/l inhibits growth of pancreatic cancer cell through up-regulating expression of HRTA3 and promoting HTRA3 mediated apoptosis. [47] In 2018, Huang et al [48] found that Paeoniflorin inhibits proliferation of human pancreatic cancer cell Pane-1 and promotes apoptosis, for which the mechanism is probably that the pathway Caspase is activated.…”

“…found that Paeoniflorin exhibits potential anticancer effect through inhibiting pathways MMP‐9 and ERK while increasing apoptosis of pancreatic cancer cell panc‐1. Based on studies performed in recent years, it is found Paeoniflorin combined with gemcitabine inhibits pathways EGFR/MAPK/ERK and ErbB3/PI3K/Akt, and increases proliferation of pancreatic cancer cell ErbB3 . Some other studies show that Paeoniflorin in concentration of 1000 μmol/l inhibits growth of pancreatic cancer cell through up‐regulating expression of HRTA3 and promoting HTRA3 mediated apoptosis .…”

“…Inhibit activity of ErbB3 directly and increase expression of Gemcitabine in ErbB3 cell line [46] 0-1000 lmol/l Pancreatic cancer cell lines Capan-1, MIAPaCa-2…”

Paeoniflorin inhibits IL‑1β‑induced MMP secretion via the NF‑κB pathway in chondrocytes

“…Paeoniflorin, a pinane monoterpene glucoside, was first isolated from plants in the Ranunculaceae family in the 1960s (8). Recent studies have reported that paeoniflorin exhibits a number of pharmacological activities, including anti-cancer, anti-inflammation, anti-pulmonary fibrosis and anti-spasmodic effects (9)(10)(11). In nucleus pulposus cells, paeoniflorin serves an anti-apoptotic role via regulating B-cell lymphoma-2 family and caspase expression (12).…”

Paeoniflorin inhibits the growth of bladder carcinoma via deactivation of STAT3

“…Today, there is interest in studying the therapeutic effects of Pae on different cancer types. In previous pharmacological investigations, Pae was confirmed to inhibit the growth of human pancreatic cancer, gastric carcinoma cells, colorectal carcinoma cells, and glioma cells (12)(13)(14)(15). A new study (16) recently reported the anti-proliferative properties of RPA extraction in treating BCa, both in vitro and in vivo.…”