Unexpected inhibitory effects against eeAChE could be found for a newly synthesized class of caffeic acid phenethyl ester (CAPE) derivatives. Thus, phenethyl-(E)-3-(3,5-dimethoxy-4-phenethoxyphenyl)-acrylate (Ki=1.97+/-0.38muM, Ki =2.44+/-0.07muM) and 4-(2-(((E)-3-(3,4-bis(benzyloxy)phenyl)acryloyl)oxy)ethyl)-1,2-phenylene (2E,2'E)-bis(3-(3,4-bis(benzyloxy)phenyl)acrylate) (Ki=0.72+/-0.31muM, Ki =1.80+/-0.21muM) showed very good inhibition of eeAChE, while being non cytotoxic for malignant human cancer cells and non-malignant mouse fibroblasts. Also, they are weak inhibitors for BChE (from equine serum).
SCOPE: Caffeic acid phenethyl ester (CAPE), a bioactive component of propolis, is considered as a new anti-cancer agent. Oral squamous cell carcinoma (OSCC) is the most common oral cancer with unsatisfying survival. N-myc downstream regulated family genes (NDRGs) involve in numerous physiological processes. We investigated the anti-cancer effect of CAPE on OSCC and related mechanisms. METHODS AND RESULTS: Cell proliferation assay, western blot, gene transfection and knockdown, and reporter assay were applied. We showed that CAPE attenuated OSCC cell proliferation and invasion in vitro, and safely and effectively inhibited OSCC cell growth in a xenograft animal model. CAPE treatment induced NDRG1, but not NDRG2 and NDRG3, expression in OSCC cells as determined by western blot, RT-qPCR, and reporter assay. The 5'-deletion assay demonstrated that CAPE increased NDRG1 promoter activity depending on the region of -128 to +46 of the 5'-flanking of NDRG1 gene. NDRG1 gene knockdown attenuated CAPE anti-growth effect on OSCC cells. CAPE activated mitogen-activated protein kinase (MAPK) signaling pathway. The extracellular signal regulated kinase (ERK) inhibitor (PD0325901) and ERK1 knockdown blocked CAPE-induced NDRG1 expression in OSCC cells. CONCLUSION: CAPE activated MAPK signaling pathway and increased NDRG1 expression through phosphorylation of ERK1/2 to repress OSCC cells growth.
Title: Caffeic acid phenethyl ester protects the brain against hexavalent chromium toxicity by enhancing endogenous antioxidants and modulating the JAK/STAT signaling pathway Mahmoud AM, Abd El-Twab SM Ref: Biomed Pharmacother, 91:303, 2017 : PubMed
Hexavalent chromium [Cr(VI)] is commonly used in industry, and is a proven toxin and carcinogen. However, the information regarding its neurotoxic mechanism is not completely understood. The present study was designed to scrutinize the possible protective effects of caffeic acid phenethyl ester (CAPE), a bioactive phenolic of propolis extract, on Cr(VI)-induced brain injury in rats, with an emphasis on the JAK/STAT signaling pathway. Rats received 2mg/kgK2CrO4 and concurrently treated with 20mg/kg CAPE for 30 days. Cr(VI)-induced rats showed a significant increase in cerebral lipid peroxidation, nitric oxide and pro-inflammatory cytokines, with concomitantly declined antioxidants and acetylcholinesterase. CAPE attenuated oxidative stress and inflammation and enhanced antioxidant defenses in the cerebrum of rats. Cr(VI) significantly up-regulated JAK2, STAT3 and SOCS3, an effect that was reversed by CAPE. In conclusion, CAPE protects the brain against Cr(VI) toxicity through abrogation of oxidative stress, inflammation and down-regulation of JAK2/STAT3 signaling in a SOCS3-independent mechanism.
Background. The aim of the study was to analyse the effect of caffeic acid phenethyl ester (CAPE) on fluoxetine-induced hepatotoxicity in rats. Materials and Methods. Group I served as control. Group II received CAPE intraperitoneally. Group III received fluoxetine per orally. Group IV received fluoxetine and CAPE. The total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and liver enzymes including paraoxonase-1 (PON-1), aspartate transaminase, and alanine transaminase levels were measured. Liver tissues were processed histopathologically for evaluation of liver injury and to validate the serum enzyme levels. Results. An increase in TOS and OSI and a decrease in TAC and PON-1 levels in serum and liver tissues of Group III were observed compared to Groups I and II. After treatment with CAPE, the level of TOS and OSI decreased while TAC and PON-1 increased in serum and liver in Group IV. Histopathological examination of the liver revealed hepatic injury after fluoxetine treatment and reduction of injury with CAPE treatment. Conclusion. Our results suggested that CAPE treatment provided protection against fluoxetine toxicity. Following CAPE treatment with fluoxetine-induced hepatotoxicity, TOS and OSI levels decreased, whereas PON-1 and TAC increased in the serum and liver.
Title: The effect of caffeic acid phenethyl ester (CAPE) on metabolic enzymes including acetylcholinesterase, butyrylcholinesterase, glutathione S-transferase, lactoperoxidase, and carbonic anhydrase isoenzymes I, II, IX, and XII Gulcin I, Scozzafava A, Supuran CT, Akincioglu H, Koksal Z, Turkan F, Alwasel S Ref: J Enzyme Inhib Med Chem, :1, 2015 : PubMed
Caffeic acid phenethyl ester (CAPE) is an active component of honeybee propolis extracts. Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread and intensively studied metalloenzymes present in higher vertebrates including humans as many diverse isoforms. Acetylcholinesterase (AChE) is responsible for acetyl choline (ACh) hydrolysis and plays a fundamental role in nerve impulse transmission by terminating the action of the ACh neurotransmitter at cholinergic synapses and neuromuscular junctions. Butyrylcholinesterase (BChE) is another enzyme abundantly present in the liver and released into blood in a soluble form. Lactoperoxidase (LPO) is an enzyme involved in fighting pathogenic microorganisms whereas glutathione S-transferases (GSTs) are dimeric proteins present both in prokaryotic and eukaryotic organisms and involved in cellular detoxification mechanisms. In the present study, the inhibition effect of CAPE on human carbonic anhydrase (hCA) isoforms I, II, IX, and XII, AChE, BChE, LPO, and GST was evaluated. CAPE inhibited these enzymes with Kis in the range between micromolar to picomolar. The best inhibitory effect was observed against AChE and BChE.
Title: Protective role of caffeic acid phenethyl ester on serum cholinesterase inhibition by acute exposure to diazinon in rats Oguzhanoglu E, Andac AC, Tufek A, Yavuz L, Vural H, Gokalp O Ref: Turk J Med Sci, 44:115, 2014 : PubMed
AIM: To evaluate whether caffeic acid phenethyl ester (CAPE), a flavonoid-like natural compound plentifully found in beeswax, has a protective effect on diazinon-induced serum cholinesterase (ChE) inhibition in rats. MATERIALS AND METHODS: Animals were divided into 4 groups. The first animal group was not treated with any substance. The second animal group was orally given a 200 mg/kg body weight (bw) sublethal dose of diazinon. The third animal group was injected intraperitoneally with 2.84 mg (10 micromol)/kg bw of CAPE 1 day prior to administration of 200 mg/kg bw of diazinon orally. The fourth animal group was intraperitoneally injected with 2.84 mg (10 tmol)/kg bw of CAPE 30 min after 200 mg/kg bw of diazinon was orally administered. RESULTS: Analysis of the animal blood samples obtained 48 h after diazinon administration revealed that diazinon decreased serum ChE activity by 75%, while CAPE administration 24 h prior to and 30 min following diazinon application improved serum ChE activity by 25%-32% as compared to levels with diazinon administration only. In silico studies suggest that CAPE prevents diazinon from binding to butyryl ChE due to a higher binding affinity than that of diazinon. CONCLUSION: Our laboratory findings suggest that CAPE plays a protective role against butyryl ChE inhibition by diazinon.
Title: Effects of intralipid and caffeic acid phenethyl ester on neurotoxicity, oxidative stress, and acetylcholinesterase activity in acute chlorpyriphos intoxication Ozkan U, Osun A, Basarslan K, Senol S, Kaplan I, Alp H Ref: Int J Clin Exp Med, 7:837, 2014 : PubMed
Chlorpyriphos is one of the most widely used organophosphate (OP) insecticide in agriculture with potential toxicity. Current post-exposure treatments consist of anti-cholinergic drugs and oxime compounds. We studied the effects of intralipid and caffeic acid phenethyl ester (CAPE) on chlorpyriphos toxicity to compose an alternative or supportive treatment for OP poisoning. METHODS: Forty-nine rats were randomly divided into seven groups. Chlorpyriphos was administered for toxicity. Intralipid (IL) and CAPE administered immediately after chlorpyriphos. Serum acetylcholinesterase (AChE) level, total oxidant status (TOS), total antioxidant response (TAR), and histologic examination of cerebellum and brain tissue with Hematoxylin-Eosin and immunohistochemical dyes were examined. RESULTS: Serum enzym levels showed that chlorpyriphos and CAPE inhibited AChE while IL alone had no effect, chlorpyriphos and CAPE intensifies the inhibition effect. Significant difference at AChE levels between the chlorpyriphos+IL and chlorpyriphos+CAPE verified that IL has a protective effect on AChE inhibition. TAR levels were significantly increased in all groups except chlorpyriphos group, TOS levels revealed that CAPE and IL decrease the amount of oxidative stress. Histologic examination revealed that neuronal degeneration was slightly decreased at chlorpyriphos+IL group, but CAPE had a significant effect on protection of neuronal degeneration. CONCLUSION: The results of this study gave us three key points. 1) AChE activity is important for diagnosis of OP intoxication but it has no value for determining the neuro-degeneration. 2) CAPE inhibits AChE activity and may increase the muscarinic-nicotinic hyperactivation. Therefore it should not be used for treatment of OP intoxication. 3) IL decreases the severity of neurodegeneration and symptoms of OP intoxication and it can be used as a supportive agent.
Title: Optimization of lipase-catalyzed synthesis of caffeic acid phenethyl ester in ionic liquids by response surface methodology Ha SH, Van Anh T, Koo YM Ref: Bioprocess Biosyst Eng, 36:799, 2013 : PubMed
Lipase-catalyzed caffeic acid phenethyl ester (CAPE) synthesis in ionic liquid, 1-ethyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([Emim][Tf(2)N]), was investigated in this study. The effects of several reaction conditions, including reaction time, reaction temperature, substrate molar ratio of phenethyl alcohol to caffeic acid (CA), and weight ratio of enzyme to CA, on CAPE yield were examined. In a single parameter study, the highest CAPE yield in [Emim][Tf(2)N] was obtained at 70 degreesC with a substrate molar ratio of 30:1 and weight ratio of enzyme to CA of 15:1. Based on these results, response surface methodology (RSM) with a 3-level-4-factor central composite rotatable design (CCRD) was adopted to evaluate enzymatic synthesis of CAPE in [Emim][Tf(2)N]. The four major factors were reaction time (36-60 h), reaction temperature (65-75 degreesC), substrate molar ratio of phenethyl alcohol to CA (20:1-40:1), and weight ratio of enzyme to CA (10:1-20:1). A quadratic equation model was used to analyze the experimental data at a 95 % confidence level (p < 0.05). A maximum conversion yield of 99.8 % was obtained under the optimized reaction conditions [60 h, 73.7 degreesC, substrate molar ratio of phenethyl alcohol to CA (27.1:1), and weight ratio of enzyme to CA (17.8:1)] established by our statistical method, whereas the experimental conversion yield was 96.6 +/- 2 %.
Caffeic acid phenethyl ester (CAPE), one of the major components of propolis (honeybee resin), has demonstrated a wide spectrum of activities including suppression of eicosanoids by inhibition of cyclooxygenase-1 and cyclooxygenase-2 enzyme activities. The aim of this study was to investigate the effect of CAPE on basal and secretagogues-stimulated gastric acid secretion in vitro. In the isolated, lumen-perfused, stomach preparation of mouse, CAPE (10-100 microM) did not affect the basal gastric acid secretion nor the secretion stimulated by histamine, pentagastrin, isobutyl methylxanthine and high levels of K+. By contrast, CAPE increased the gastric acid secretion induced by the muscarinic receptor agonist, 5-methylfurmethide (5-MEF). CAPE also inhibited the acetylcholinesterase activity in an in vitro colorimetric assay. Eserine (10 microM), a well known acetylcholinesterase inhibitor, also increased 5-MEF-stimulated acid secretion. Our results show that CAPE increases gastric acid secretion stimulated by an acetylcholine agonist receptor likely through inhibition of acetylcholinesterase activity.
