Interaction of olive oil-based propolis and caffeic acid phenethyl ester with methylprednisolone used in the treatment of human acute myeloid leukemia.

BACKGROUND: Methylprednisolone (MP) is a pharmaceutical agent employed in the management of Leukemia, which is a systemic malignancy that arises from abnormalities in the hematological system. Numerous investigations in the field of cancer research have directed their attention towards propolis, a natural substance with significant potential as a treatment-supportive agent. Its utilization aims to mitigate the potential adverse effects associated with chemotherapy medications. The objective of this study was to examine the impact of olive oil-based propolis (OEP) and caffeic acid phenethyl ester (CAPE) on the treatment of acute myeloid leukemia, as well as to determine if they exhibit a synergistic effect when combined with the therapeutic support product methylprednisolone. METHODS AND RESULTS: The proliferation of HL-60 cells was quantified using the WST-8 kit. The PI Staining technique was employed to do cell cycle analysis of DNA in cells subjected to OEP, CAPE, and MP, with subsequent measurement by flow cytometry. The apoptotic status of cells was determined by analyzing them using flow cytometry after staining with the Annexin V-APC kit. The quantification of apoptotic gene expression levels was conducted in HL-60 cells. In HL-60 cells, the IC50 dosages of CAPE and MP were determined to be 1 × 10- 6 M and 5 × 10- 4 M, respectively. The HL-60 cells were subjected to apoptosis and halted in the G0/G1 and G2/M phases of the cell cycle after being treated with MP, CAPE, and OEP. CONCLUSIONS: Propolis and its constituents have the potential to serve as effective adjunctive therapies in chemotherapy.

The anticancer impacts of free and liposomal caffeic acid phenethyl ester (CAPE) on melanoma cell line (A375).

The deadliest type of skin cancer, malignant melanoma, is also the reason for the majority of skin cancer-related deaths. The objective of this article was to investigate the efficiency of free caffeic acid phenethyl ester (CAPE) and liposomal CAPE in inducing apoptosis in melanoma cells (A375) in in vitro. CAPE was loaded into liposomes made up of hydrogenated soybean phosphatidylcholine, cholesterol, and 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000], and their physicochemical properties were assessed. (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test was performed for comparing the cytotoxicity of free CAPE and liposomal CAPE at dosages of 10, 15, 25, 50, 75 and the highest dose of 100 µg/mL for period of 24 and 48 h on A375 cell line to calculate IC50. Apoptosis and necrosis were evaluated in A375 melanoma cancer cells using flow cytometry. Atomic force microscopy was utilized to determine the nanomechanical attributes of the membrane structure of A375 cells. To determine whether there were any effects on apoptosis, the expression of PI3K/AKT1 and BAX/BCL2 genes was analyzed using the real-time polymerase chain reaction technique. According to our results, the maximum amount of drug release from nanoliposomes was determined to be 91% and the encapsulation efficiency of CAPE in liposomes was 85.24%. Also, the release of free CAPE was assessed to be 97%. Compared with liposomal CAPE, free CAPE showed a greater effect on reducing the cancer cell survival after 24 and 48 h. Therefore, IC50 values of A375 cells treated with free and liposomal CAPE were calculated as 47.34 and 63.39 µg/mL for 24 h. After 48 h of incubation of A375 cells with free and liposomal CAPE, IC50 values were determined as 30.55 and 44.83 µg/mL, respectively. The flow cytometry analysis revealed that the apoptosis induced in A375 cancer cells was greater when treated with free CAPE than when treated with liposomal CAPE. The highest nanomechanical changes in the amount of cell adhesion forces, and elastic modulus value were seen in free CAPE. Subsequently, the greatest decrease in PI3K/AKT1 gene expression ratio occurred in free CAPE.

The neuroprotective effects of caffeic acid phenethyl ester against methamphetamine-induced neurotoxicity.

Methamphetamine (METH) is a highly abused substance on a global scale and has the capacity to elicit toxicity within the central nervous system. The neurotoxicity induced by METH encompasses neuronal degeneration and cellular demise within the substantia nigra-striatum and hippocampus. Caffeic acid phenethyl ester (CAPE), a constituent of propolis, is a diminutive compound that demonstrates antioxidative and anti-inflammatory characteristics. Numerous investigations have demonstrated the safeguarding effects of CAPE in various neurodegenerative ailments. Our hypothesis posits that CAPE may exert a neuroprotective influence on METH-induced neurotoxicity via specific mechanisms. In order to validate the hypothesis, a series of experimental techniques including behavioral tests, immunofluorescence labeling, RNA sequencing, and western blotting were employed to investigate the neurotoxic effects of METH and the potential protective effects of CAPE. The results of our study demonstrate that CAPE effectively ameliorates cognitive memory deficits and anxiety symptoms induced by METH in mice. Furthermore, CAPE has been observed to attenuate the upregulation of neurotoxicity-associated proteins that are induced by METH exposure and also reduced the loss of hippocampal neurons in mice. Moreover, transcriptomics analysis was conducted to determine alterations in gene expression within the hippocampus of mice. Subsequently, bioinformatics analysis was employed to investigate the divergent outcomes and identify potential key genes. Interferon-stimulated gene 15 (ISG15) was successfully identified and confirmed through RT-qPCR, western blotting, and immunofluorescence techniques. Our research findings unequivocally demonstrated the neuroprotective effect of CAPE against METH-induced neurotoxicity, with ISG15 may have an important role in the underlying protective mechanism. These results offer novel perspectives on the treatment of METH-induced neurotoxicity.

Single and multiple inhibitors of the biosynthesis of 5-, 12-, 15-lipoxygenase products derived from cinnamyl-3,4-dihydroxy-α-cyanocinnamate: Synthesis and structure-activity relationship.

The involvement of lipoxygenases in various pathologies, combined with the unavailability of safe and effective inhibitors of the biosynthesis of their products, is a source of inspiration for the development of new inhibitors. Based on a structural analysis of known inhibitors of lipoxygenase products biosynthesis, a comprehensive structure-activity study was carried out, which led to the discovery of several novel compounds (16a-c, 17a) demonstrating promising potency to inhibit the biosynthesis of products of 5-, 12- and 15-LO. Compounds 16b and 16c outperformed zileuton (1), the only FDA-approved 5-LO inhibitor, as well as known inhibitors such as caffeic acid phenethyl ester (CAPE (2)) and cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC (4)). However, the introduction of a cyano group at the α-position of the carbonyl abolished the activity. Compounds 16a and 17a also inhibited the biosynthesis of 12- and 15-LO products. Compounds 16a, 17a far surpassed baicalein, a known 12-LO inhibitor, as inhibitors of 12-LO products biosynthesis. Compound 17a and CDC (4) showed equivalent inhibition of LO products, proposing that the double bond in the ester moiety is not necessary for the inhibitory activity. The introduction of the cyano group, as in compound 17a, at the α-position of the carbonyl in compound 16a significantly reduced the inhibitory activity against the biosynthesis of 15-LO products. In addition to the interactions with residues His372 and Phe421 also found with zileuton and CAPE, compounds 16a and 16c each interact with residue His367 as shown by molecular docking. This new interaction may explain their high affinity with the 5-LO active site.

Caffeic acid phenethyl ester ameliorates titanium particle-induced bone loss and inflammatory reaction in a mouse acute model.

With the increasing clinical application of dental and orthopedic implants, the problem of peri-implant osteolysis has attracted attention. The inflammatory response and osteoclast differentiation induced by wear particles play an important role in peri-implant bone loss. However, the treatment of peri-implant osteolysis is still lacking. In the present study, we investigated the effect of caffeic acid phenethyl ester (CAPE) on titanium particles induced bone loss in a mouse model. We found that CAPE significantly suppressed titanium particle-induced bone loss in vivo. CAPE treatment decreased ratio of nuclear factor kappa B receptor activator ligand (RANKL)/osteoprotegerin (OPG) and subsequently reduced osteoclastogenesis in the mouse model. In addition, CAPE downregulated the expression and secretion of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) stimulated by titanium particles in vivo. In summary, we conclude that CAPE prevent the titanium particles-induced bone loss.

Caffeic acid phenethyl ester suppresses intestinal FXR signaling and ameliorates nonalcoholic fatty liver disease by inhibiting bacterial bile salt hydrolase activity.

Propolis is commonly used in traditional Chinese medicine. Studies have demonstrated the therapeutic effects of propolis extracts and its major bioactive compound caffeic acid phenethyl ester (CAPE) on obesity and diabetes. Herein, CAPE was found to have pharmacological activity against nonalcoholic fatty liver disease (NAFLD) in diet-induced obese mice. CAPE, previously reported as an inhibitor of bacterial bile salt hydrolase (BSH), inhibited BSH enzymatic activity in the gut microbiota when administered to mice. Upon BSH inhibition by CAPE, levels of tauro-ß-muricholic acid were increased in the intestine and selectively suppressed intestinal farnesoid X receptor (FXR) signaling. This resulted in lowering of the ceramides in the intestine that resulted from increased diet-induced obesity. Elevated intestinal ceramides are transported to the liver where they promoted fat production. Lowering FXR signaling was also accompanied by increased GLP-1 secretion. In support of this pathway, the therapeutic effects of CAPE on NAFLD were absent in intestinal FXR-deficient mice, and supplementation of mice with C16-ceramide significantly exacerbated hepatic steatosis. Treatment of mice with an antibiotic cocktail to deplete BSH-producing bacteria also abrogated the therapeutic activity of CAPE against NAFLD. These findings demonstrate that CAPE ameliorates obesity-related steatosis at least partly through the gut microbiota-bile acid-FXR pathway via inhibiting bacterial BSH activity and suggests that propolis enriched with CAPE might serve as a promising therapeutic agent for the treatment of NAFLD.

Caffeic acid phenethyl ester: A review on its pharmacological importance, and its association with free radicals, COVID-19, and radiotherapy.

Caffeic acid phenethyl ester (CAPE), a main active component of propolis and a flavonoid, is one of the natural products that has attracted attention in recent years. CAPE, which has many properties such as anti-cancer, anti-inflammatory, antioxidant, antibacterial and anti-fungal, has shown many pharmacological potentials, including protective effects on multiple organs. Interestingly, molecular docking studies showed the possibility of binding of CAPE with replication enzyme. In addition, it was seen that in order to increase the binding security of the replication enzyme and CAPE, modifications can be made at three sites on the CAPE molecule, which leads to the possibility of the compound working more powerfully and usefully to prevent the proliferation of cancer cells and reduce its rate. Also, it was found that CAPE has an inhibitory effect against the main protease enzyme and may be effective in the treatment of SARS-CoV-2. This review covers in detail the importance of CAPE in alternative medicine, its pharmacological value, its potential as a cancer anti-proliferative agent, its dual role in radioprotection and radiosensitization, and its use against coronavirus disease 2019 (COVID-19).

Caffeic Acid Phenethyl Ester and Caffeamide Derivatives Suppress Oral Squamous Cell Carcinoma Cells.

Caffeic acid phenethyl ester (CAPE) contains antibiotic and anticancer activities. Therefore, we aimed to investigate the anticancer properties and mechanisms of CAPE and caffeamide derivatives in the oral squamous cell carcinoma cell (OSCC) lines SAS and OECM-1. The anti-OSCC effects of CAPE and the caffeamide derivatives (26G, 36C, 36H, 36K, and 36M) were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Cell cycle and total reactive oxygen species (ROS) production were analyzed using flow cytometry. The relative protein expression of malignant phenotypes was determined via Western blot analysis. The results showed that 26G and 36M were more cytotoxic than the other compounds in SAS cells. After 26G or 36M treatment for 48 h, cell cycle S phase or G2/M phase arrest was induced, and cellular ROS increased at 24 h, and then decreased at 48 h in both cell lines. The expression levels of cell cycle regulatory and anti-ROS proteins were downregulated. In addition, 26G or 36M treatment inhibited malignant phenotypes through mTOR-ULK1-P62-LC3 autophagic signaling activated by ROS generation. These results showed that 26G and 36M induce cancer cell death by activating autophagy signaling, which is correlated with altered cellular oxidative stress.

Caffeic Acid Phenethyl Ester (CAPE) Synergistically Enhances Paclitaxel Activity in Ovarian Cancer Cells.

Caffeic acid phenethyl ester (CAPE) belongs to the phenols found in propolis. It has already shown strong antiproliferative, cytotoxic and pro-apoptotic activities against head and neck cancers and against breast, colorectal, lung and leukemia cancer cells. Ovarian cancer is one of the most dangerous gynecological cancers. Its treatment involves intensive chemotherapy with platinum salts and paclitaxel (PTX). The purpose of this study was to evaluate whether the combined use of CAPE and paclitaxel increases the effectiveness of chemotherapeutic agents. The experiment was performed on three ovarian cancer lines: OV7, HTB78, and CRL1572. The effect of the tested compounds was assessed using H-E staining, a wound-healing test, MTT and the cell death detection ELISAPLUS test. The experiment proved that very low doses of PTX (10 nM) showed a cytotoxic effect against all the cell lines tested. Also, the selected doses of CAPE had a cytotoxic effect on the tested ovarian cancer cells. An increase in the cytotoxic effect was observed in the OV7 line after the simultaneous administration of 10 nM PTX and 100 µM CAPE. The increase in the cytotoxicity was dependent on the CAPE dosage (50 vs. 100 µM) and on the duration of the experiment. In the other cell lines tested, the cytotoxic effect of PTX did not increase after the CAPE administration. The administration of PTX together with CAPE increased the percentage of apoptotic cells in the tested ovarian cancer cell lines. Moreover, the simultaneous administration of PTX and CAPE enhanced the anti-migration activity of the chemotherapeutic used in this study.

Effects of Temperature, Metal Ions and Biosurfactants on Interaction Mechanism between Caffeic Acid Phenethyl Ester and Hemoglobin.

Caffeic acid phenylethyl ester (CAPE) is a natural polyphenol extracted from propolis, which is reported to have several pharmacological effects such as antibacterial, antitumor, antioxidant and anti-inflammatory activities. Hemoglobin (Hb) is closely related to the transport of drugs, and some drugs, including CAPE, can lead to a change in Hb concentration. Herein, the effects of temperature, metal ions and biosurfactants on the interaction between CAPE and Hb were studied using ultraviolet-visible spectroscopy (UV-Vis), fluorescence spectroscopy, circular dichroism (CD), dynamic light scattering (DLS) and molecular docking analysis. The results showed that the addition of CAPE led to changes in the microenvironment of Hb amino acid residues as well as the secondary structure of Hb. Hydrogen bonding and van der Waals force were found to be the main driving forces for the interaction between CAPE and Hb through fluorescence spectroscopy and thermodynamic parameter data. The results of fluorescence spectroscopy also showed that lowering the temperature, adding biosurfactants (sodium cholate (NaC) and sodium deoxycholate (NaDC)) and the presence of Cu2+ increased the binding force between CAPE and Hb. These results provide useful data for the targeted delivery and absorption of CAPE and other drugs.

The Phenolic Profile and Anti-Inflammatory Effect of Ethanolic Extract of Polish Propolis on Activated Human Gingival Fibroblasts-1 Cell Line.

Propolis, owing to its antibacterial and anti-inflammatory properties, acts as a cariostatic agent, capable of preventing the accumulation of dental plaque and inhibiting inflammation. The anti-inflammatory properties of propolis are attributed to caffeic acid phenethyl ester (CAPE), which is present in European propolis. The objective of the conducted study was to assess the anti-inflammatory effects of the Polish ethanolic extract of propolis (EEP) and isolated CAPE on stimulated with LPS and IFN-α, as well as the combination of LPS and IFN-α. The cytotoxicity of the tested compounds was determined using the MTT assay. The concentrations of specific cytokines released by the HGF-1 cell line following treatment with EEP (25-50 µg/mL) or CAPE (25-50 µg/mL) were assessed in the culture supernatant. In the tested concentrations, both CAPE and EEP did not exert cytotoxic effects. Our results demonstrate that CAPE reduces TNF-α and IL-6 in contrast to EEP. Propolis seems effective in stimulating HGF-1 to release IL-6 and IL-8. A statistically significant difference was observed for IL-8 in HGF-1 stimulated by LPS+IFN-α and treated EEP at a concentration of 50 µg/mL (p = 0.021201). Moreover, we observed that CAPE demonstrates a stronger interaction with IL-8 compared to EEP, especially when CAPE was administered at a concentration of 50 µg/mL after LPS + IFN-α stimulation (p = 0.0005). Analysis of the phenolic profile performed by high-performance liquid chromatography allowed identification and quantification in the EEP sample of six phenolic acids, five flavonoids, and one aromatic ester-CAPE. Propolis and its compound-CAPE-exhibit immunomodulatory properties that influence the inflammatory process. Further studies may contribute to explaining the immunomodulatory action of EEP and CAPE and bring comprehensive conclusions.

Phosphorylated walnut protein/chitosan nanocomplexes as promising carriers for encapsulation of caffeic acid phenethyl ester.

BACKGROUND: Walnut proteins display poor solubility and dispersity under acidic pH conditions, which limits their application in acidic beverages and foods. This study aimed to fabricate stable nanocomplexes between phosphorylated walnut protein (PWPI) and chitosan (CS) in an acidic pH and to investigate the encapsulation capacity of the complexes. RESULTS: The PWPI/CS nanocomplexes prepared at a mass ratio of 2:1 showed small Z-average sizes (approximately 285 nm at pH 5.5 and 222 nm at pH 3.5) with a narrow particle distribution (polydispersity index <0.3). Caffeic acid phenethyl ester (CAPE) can be effectively encapsulated into PWPI/CS with improved solubility. Circular dichroism analysis indicated that PWPI/CS and CAPE-loaded PWPI/CS (PWPI/CS-CAPE) had reduced α-helical content and increased ß-sheet content. Fourier transform infrared spectroscopy analysis further identified the different driving forces for the complexation of PWPI and CS at pH 3.5 and 5.5 and confirmed the successful encapsulation of CAPE. The rheological results revealed that the PWPI/CS and PWPI/CS-CAPE formed at pH 3.5 (PWPI/CS-CAPE-3.5) had a higher apparent viscosity and better viscoelasticity than the complexes formed at pH 5.5. The PWPI/CS-CAPE-3.5 also showed good stability under heat treatment, salt treatment, and long-term storage. The PWPI/CS-CAPE complexes showed controlled release of CAPE. CONCLUSION: Walnut protein and chitosan nanocomplexes prepared at acidic pH levels were stable and promising carriers for CAPE, which could expand the application of walnut proteins in the food industry. © 2023 Society of Chemical Industry.

Intralipid and caffeic acid phenethyl ester reverse the neurotoxic effects of organophosphate poisoning in rats.

Background: Organophosphate (Op)-containing herbicides continue to be widely used in the world. Although its usage and intoxication are widespread, the studies on organophosphate-induced neurotoxicity and treatment protocols are very few in the literature. Aims: This study aimed to investigate any potential effects of caffeic acid phenyl ester with/without intralipid on neurotoxicity produced by acute intoxication of glyphosate isopropylamine in an experimental rat model. Materials And Methods: Forty-nine wistar albino rats were randomly allotted into seven experimental groups: I, control; II, intralipid (IL); III, caffeic acid phenyl esther (CAPE); IV, glyphosate isopropylamine (GI); V, GI + IL; VI, GI + CAPE; and VII, GI + IL + CAPE. Total antioxidant and oxidant status levels were gauged, and the oxidative stress index was calculated in the serum samples. On the other hand, the tissues were analyzed with hematoxylin-eosin (HE) staining protocol and counted up by immunohistochemical method. Statistical evaluations were conducted using SPSS 11.5 for Windows (SPSS, Chicago, IL, USA). Results: Compared to the control, IL, and GI + IL + CAPE groups, the GI group significantly decreased the total antioxidant levels in brain tissues. In a supportive nature, a significant increase in the oxidative site index (OSI) in the GI group compared to other groups. Especially standing out point of these findings is the significant difference between the GI + IL + CAPE and the GI group. Parallelly, histopathological analysis extended severe neurotoxicity in the GI group. Neurotoxic status was reduced significantly in the GI + CAPE + IL group. The histopathologic examinations confirmed biochemical results. The results also revealed that CAPE and IL, probably their antioxidant effects, have a rehabilitative effect on neurotoxicity caused by GI. Conclusion: Therefore, CAPE and IL may function as potential cleansing and scavenger agents for supportive therapy regarding tissue damage or facilitate the therapeutic effects of the routine treatment of the patient with GI poisoning.

Caffeic Acid Phenethyl Ester Induces Vascular Endothelial Growth Factor Production and Inhibits CXCL10 Production in Human Dental Pulp Cells.

The survival rate of root non-vital teeth is lower than that of vital teeth. Therefore, to preserve the dental pulp is very important. The vascular endothelial growth factor (VEGF) is the most potent angiogenic factor involved in the vitality of dental pulp including reparative dentin formation. Caffeic acid phenethyl ester (CAPE) is a physiologically active substance of propolis and has some bioactivities such as anti-inflammatory effects. However, there are no reports on the effects of CAPE on dental pulp inflammation. In this study, we investigated the effects of CAPE on VEGF and inflammatory cytokine production in human dental pulp cells (HDPCs) to apply CAPE to an ideal dental pulp protective agent. We found that CAPE induced VEGF production from HDPCs. Moreover, CAPE induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK), and stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) in HDPCs. Furthermore, CAPE inhibited C-X-C motif chemokine ligand 10 (CXCL10) production in Pam3CSK4- and tumor necrosis factor-alpha (TNF-α)-stimulated HDPCs. In conclusion, these results suggest that CAPE might be useful as a novel biological material for vital pulp therapy by exerting the effects of VEGF production and anti-inflammatory activities.

Combination treatment of docetaxel with caffeic acid phenethyl ester suppresses the survival and the proliferation of docetaxel-resistant prostate cancer cells via induction of apoptosis and metabolism interference.

BACKGROUND: Docetaxel has been approved by USFDA as a first-line treatment for castration-resistant prostate cancer (CRPC) patients. Patients receiving androgen deprivation therapy along with docetaxel result in superior survival, lower serum prostate specific antigen (PSA) level, and better quality of life. However, a significant proportion of these patients ultimately develop resistance to docetaxel within months. Caffeic acid phenethyl ester (CAPE), one of the main bioactive components extracted from the propolis, has been reported to be effective for repressing the tumor growth, the migration and invasion of prostate cancer (PCa) cells, as well as the downstream signaling and stability of androgen receptor (AR). We hence determined if combination treatment of docetaxel with CAPE can suppress the proliferation and the survival of docetaxel-resistant PCa cells. METHODS: We established docetaxel-resistant PC/DX25 and DU/DX50 CRPC cell lines from PC-3 and DU-145 human PCa cells, respectively. Proliferation assay, MTT assay, flow cytometry with Annexin V staining, Comet Assay, and nude mice xenograft model were applied to determine the effects of combination treatment on cell proliferation and survival of the docetaxel-resistant PCa cells. Micro-Western Array (MWA) and qRT-PCR were used to investigate the molecular mechanism lying underneath. RESULTS: Combination treatment effectively suppressed the proliferation, survival and tumor growth of docetaxel-resistant PCa cells both in vitro and in nude mice. Comet assay and flow cytometry indicated that combination treatment induced apoptosis in docetaxel-resistant PCa cells. MWA and Western blotting assay revealed that combination treatment suppressed protein expression of Bcl-2, AKT2, c-Myc, apoptosis and caspase activation inhibitor (AVEN), pyruvate kinase M2 (PKM2) but increased protein expression of Bax, caspase 3, cytochrome c, glucose-6-phosphate dehydrogenase (G6PD) and acylglycerol kinase (AGK). Overexpression of Bcl-2 in the docetaxel-resistant PCa cells enhanced cell proliferation of docetaxel-resistant PCa cells under combination treatment. Analysis with qRT-PCR suggested that combination treatment decreased cholesterol biosynthesis genes DHCR24 (24-dehydrocholesterol reductase) and LSS (lanosterol synthase) but increased genes involved in glycolysis and TCA cycle. CONCLUSIONS: Combination treatment of docetaxel with CAPE effectively suppressed the proliferation and survival of docetaxel-resistant PCa cells via inhibition of Bcl-2 and c-Myc as well as induction of metabolism interference. Combination treatment can be beneficial for patients with docetaxel-resistant PCa.

Role of inflammation and oxidative stress in tissue damage associated with cystic fibrosis: CAPE as a future therapeutic strategy.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the synthesis of the CFTR protein, a chloride channel. The gene has approximately 2000 known mutations and all of them affect in some degree the protein function, which makes the pathophysiological manifestations to be multisystemic, mainly affecting the respiratory, gastrointestinal, endocrine, and reproductive tracts. Currently, the treatment of the disease is restricted to controlling symptoms and, more recently, a group of drugs that act directly on the defective protein, known as CFTR modulators, was developed. However, their high cost and difficult access mean that their use is still very restricted. It is important to search for safe and low-cost alternative therapies for CF and, in this context, natural compounds and, mainly, caffeic acid phenethyl ester (CAPE) appear as promising strategies to assist in the treatment of the disease. CAPE is a compound derived from propolis extracts that has antioxidant and anti-inflammatory activities, covering important aspects of the pathophysiology of CF, which points to the possible benefit of its use in the disease treatment. To date, no studies have effectively tested CAPE for CF and, therefore, we intend with this review to elucidate the role of inflammation and oxidative stress for tissue damage seen in CF, associating them with CAPE actions and its pharmacologically active derivatives. In this way, we offer a theoretical basis for conducting preclinical and clinical studies relating the use of this molecule to CF.

Interaction between caffeic acid phenethyl ester and protease: monitoring by spectroscopic and molecular docking approaches.

The interaction of one anticancer drug (caffeic acid phenethyl ester; CAPE) with three proteases (trypsin, pepsin and α-chymotrypsin) has been investigated with multispectral methods and molecular docking. As an active components in propolis, the findings are of great benefit to metabolism, design, and structural modification of drugs. The results show that CAPE has an obvious ability to quench the trypsin, pepsin, or α-chymotrypsin fluorescence mainly through a static quenching procedure. Trypsin has the largest binding affinity to CAPE, and α-chymotrypsin has the smallest binding affinity to CAPE. The data obtained from thermodynamic parameters and molecular docking prove that the spontaneously interaction between CAPE and each protease is mainly due to a combination of van der Waals (vdW) force and hydrogen bond (H-bond), controlled by an enthalpy-driven process. The binding force, strength, position, and the number of H-bond are further obtained from the results of molecular docking. Through ultraviolet spectroscopy, dynamic light scattering and circular dichroism experiments, the change in the protease secondary structure induced by CAPE was observed. Additionally, the addition of protease had a positive effect on the antioxidative activity of CAPE, and α-chymotrypsin has the greatest effect on the removal of 2,2-diphenyl-1-picrylhydrazyl free radicals by CAPE.

Caffeic acid phenethyl ester induces radiosensitization via inhibition of DNA damage repair in androgen-independent prostate cancer cells.

In the present study, we evaluated the radiomodulatory potential of caffeic acid phenethyl ester (CAPE), an active component of traditional herbal medicine propolis. CAPE has been identified as a potent anticancer agent in multiple cancer types and is reported to have the dual role of radioprotection and radiosensitization. However, the radiomodulatory potential of CAPE in prostate cancer (PCa), which eventually becomes radioresistant is not known. Therefore, we studied the effect of co-treatment of CAPE and gamma radiation on androgen-independent DU145 and PC3 cells. The combination treatment sensitized PCa cells to radiation in a dose-dependent manner. The radiosensitizing effect of CAPE was observed in both cell lines. CAPE enhanced the level of ionizing radiation (IR)-induced gamma H2AX foci and cell death by apoptosis. The combination treatment also decreased the migration potential of PCa cells. This was confirmed by increased expression of E-cadherin and decrease in vimentin expression. CAPE sensitized PCa cells to radiation in vitro and induced apoptosis, augmented phosphorylation of Akt/mTOR, and hampered cell migration. At the mechanistic level, co-treatment of CAPE and IR inhibited cell growth by decreasing RAD50 and RAD51 proteins involved in DNA repair. This resulted in enhanced DNA damage and cell death. CAPE might represent a promising new adjuvant for the treatment of hormone-refractory radioresistant PCa.

In Vitro Antimicrobial Potential of CAPE and Caffeamide Derivatives against Oral Microbes.

Caffeic acid phenethyl ester (CAPE) is a natural component isolated from propolis and used in traditional medicine. We aimed to investigate the antimicrobial properties and action mechanism of CAPE and caffeamide derivatives (26G and 36M) against oral disease microbes. We resolved the minimum inhibitory and bactericidal concentrations of 26G and 36M and their stability at different temperatures and pH. We also evaluated their effect on biofilm formation and antibiotic resistance gene expression in methicillin-resistant Staphylococcus aureus (MRSA). Our results revealed that 26G and 36M showed the best anticancer and antimicrobial activities, respectively, compared with the other four caffeamide derivatives. Both 26G and 36M showed heat-dependent decreases in antimicrobial activity. The 36M derivative was stable irrespective of pH, whereas 26G was not stable under high pH conditions. Biofilm formation and antibiotic resistance-related gene expression were consistent with their respective phenotypes. This study provides evidence for the potential application of CAPE and caffeamide derivatives in dental medicine to cure or prevent oral diseases.

Lycopene and Caffeic Acid Phenethyl Ester Affect Caspase-3 Activity, but Do Not Alter the NO Pathway in Lung Tissue Damage Induced by Cisplatin.

INTRODUCTION: Antioxidants such as lycopene (LCP) and caffeic acid phenethyl ester (CAPE) represent ideal molecules for the treatment of different reactive oxygen species (ROS) associated disorders. Cisplatin is a chemotherapeutic agent, causing an increase in ROS and DNA damage, with numerous side effects, which include lung toxicity. In the presents study, we evaluated and mutually compared the potential of LCP and CAPE in preventing cisplatin-induced rat lung damage. METHODS: The study was done using pathohistological analysis and a panel of biochemical parameters that reflect lung oxidative tissue damage, inflammation, and apoptosis. RESULTS: The obtained results suggest that cisplatin (10 mg/kg) causes significant disturbances in the lung tissue morphology, followed by an increase in lipid peroxidization and protein modification. Also, a pronounced inflammatory response and cell apoptosis cascade activation was noted. Both LCP and CAPE were able to mitigate the changes, to a different extent, in oxidative damage and apoptosis progression induced by cisplatin. However, they both had limited effect on inflammation since they only prevented an increase in myeloperoxidase activity but had not been able to prevent the NO generation. CONCLUSION: It is hard to be exact in saying whether LCP or CAPE is better in preventing cis-platin-induced lung damage since they obviously possess different mechanisms of action.