Direct interaction between caffeic acid phenethyl ester and human neutrophil elastase inhibits the growth and migration of PANC-1 cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors of the digestive system, but the mechanisms of its development and progression are unclear. Inflammation is thought to be fundamental to pancreatic cancer development and caffeic acid phenethyl ester (CAPE) is an active component of honey bee resin or propolis with anti-inflammatory and anticancer activities. We investigated the inhibitory effects of CAPE on cell growth and migration induced by human neutrophil elastase (HNE) and report that HNE induced cancer cell migration at low doses and growth at higher doses. In contrast, lower CAPE doses inhibited migration and higher doses of CAPE inhibited the growth induced by HNE. HNE activity was significantly inhibited by CAPE (7.5-120 µM). Using quantitative real-time PCR and western blotting, we observed that CAPE (18-60 µM) did not affect transcription and translation of α1-antitrypsin (α1-AT), an endogenous HNE inhibitor. However, in an in silico drug target docking model, we found that CAPE directly bound to the binding pocket of HNE (25.66 kcal/mol) according to CDOCKER, and the residue of the catalytic site stabilized the interaction between CAPE and HNE as evidenced by molecular dynamic simulation. Response unit (RU) values of surface plasmon resonance (SPR) significantly increased with incremental CAPE doses (7.5-120 µM), indicating that CAPE could directly bind to HNE in a concentration-dependent manner. Thus, CAPE is an effective inhibitor of HNE via direct interaction whereby it inhibits the migration and growth of PANC-1 cells in a dose-dependent manner.

Structural Diversity and Anticancer Activity of Marine‐Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer

“…Additionally, sivelestat was reported to inhibit the migration of neutrophils in a human umbilical vein endothelial cell (HUVEC) model . The migration inhibitory ability of other NE inhibitors was also reported . Epigallocatechin‐3‐gallate (EGCG) was shown to reverse HNE‐induced migration in A549 lung cancer cells, whereas caffeic acid phenethyl ester was reported to inhibit HNE‐induced migration of PANC‐1 pancreatic cancer cells .…”

“…The migration inhibitory ability of other NE inhibitors was also reported . Epigallocatechin‐3‐gallate (EGCG) was shown to reverse HNE‐induced migration in A549 lung cancer cells, whereas caffeic acid phenethyl ester was reported to inhibit HNE‐induced migration of PANC‐1 pancreatic cancer cells . In breast cancer, the effects of elafin, an HNE inhibitor, on cancer growth and progression were reported, further supporting the role of elastase in mediating cancer progression and metastasis …”

Pancreatic Cancer (PDAC): Introduction of Evidence-Based Complementary Measures into Integrative Clinical Management

“…Over 300 constituents of propolis have been identified to date, and propolis from different geographical locations and varying compositions exhibit a range of properties [ 256 ]. In particular, one of its active ingredients, caffeic acid phenethyl ester (CAPE), has been found to exert cytotoxic and anti-proliferative, even anti-invasive effects on various human cancer, including PDAC, cell lines and a mouse model [ 257 , 258 , 259 ]. Combination of a water-soluble derivative of propolis (WSDP) with cisplatin produced interesting effects on survival of tumor-bearing mice ( Figure 13 A,B) [ 260 ].…”

Flavanomarein inhibits high glucose-stimulated epithelial-mesenchymal transition in HK-2 cells via targeting spleen tyrosine kinase

“…The complex was solvated with water in a cubic box with an explicit periodic boundary model to stimulate the environment within the cell. After creating a harmonic restraint, a standard dynamics cascade was performed, including heating, minimization, equilibration and production dynamics 41,42 .…”