Antiproliferation and radiosensitization of caffeic acid phenethyl ester on human medulloblastoma cells

Purpose: To investigate antiproliferative and radiosensitizing effects of caffeic acid phenethyl ester (CAPE) on medulloblastoma (MB) Daoy cells. Methods and materials: Daoy cells were treated with CAPE in different concentrations and assessed for cell viability, apoptosis, cell cycles, cyclin B1 expressions, radiosensitization and chemosensitization. Human astroglia SVGp12 cells were treated with CAPE to present the possible protection or complication effects in normal tissues. Results: CAPE inhibited the growth of Daoy cells in a time- and concentration-dependent manner in MTT and Trypan blue exclusion assays. Flow cytometry revealed that CAPE significantly decreased G2/M fraction, and increased the S phase fraction. Western blot demonstrated a down-regulated cyclin B1 protein expression. Pretreatment with CAPE markedly decreased the viability of irradiated Daoy cells. The sensitizer enhancement ratios (SERs) were increased in CAPE-treated Daoy cells. CAPE in doxorubicin and cisplatin did not show chemosensitizing effect. Conclusions: These findings demonstrate the antiproliferative and radiosensitizing effects of CAPE for Daoy cells, which might bring improvement to the treatment of MB. For clinical application, in vivo models are expected.     

Preferential cytotoxicity of caffeic acid phenethyl ester analogues on oral cancer cells

As part of our previous search for new compounds with improved biological activities including antibiotic, antiviral, anti-inflammatory, and tumor growth inhibition activities, we synthesized some caffeic acid phenethyl ester (CAPE)-like compounds from commercially available caffeic acid. Nine chemicals were tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on the growth of buccal mucosal fibroblast (BF), oral submucosus fibroblast (OSF), neck metastasis of Gingiva carcinoma (GNM), and tongue squamous cell carcinoma (TSCCa) cells. CAPE and its ethyl analogue show significant cytotoxicity on OSF, GNM, and TSCCa cells, but not on BF cells. The results suggest that CAPE-like compounds may be potential chemotherapy agents against oral cancer.     

Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells

Topical application of caffeic acid phenethyl ester (CAPE),a constituent of the propolis of honeybee hives, to the backsof CD-1 mice previously initiated with 7, 12-dimethylbenz[     

咖啡酸苯乙酯诱导人大肠癌细胞凋亡的研究

目的 :探讨咖啡酸苯乙酯 (caffeicacid phenethylester ,CAPE )诱导大肠癌HCT116细胞发生凋亡的作用 ,为CAPE用于大肠癌的临床治疗提供依据。方法 :采用MTT法、HE染色、AnnexinV FITC/PI双染色流式细胞术和末端脱氧核苷酸标记法(TUNEL) ,检测不同浓度CAPE作用后HCT116细胞增殖活性和细胞凋亡的变化。结果 :2 5、5 0、10 0mg/L的CAPE处理HCT116细胞 2 4h后 ,抑制率分别为12 2 0 %、2 2 44 %、3 7 86% ,细胞增殖明显受到抑制 ,呈量效依赖性 ;凋亡率分别为( 10 2 0± 0 66) %、 ( 16 60± 0 61) %、( 2 5 5 3± 3 2 7) % ,均显著高于对照组 ( 5 47± 0 93 ) % ,P <0 0 1。HE染色呈现典型的凋亡细胞形态特征。TUNEL法标记见明显的凋亡阳性细胞。结论 :CAPE可诱导体外培养的大肠癌细胞发生凋亡     

Inhibitory effect of caffeic acid phenethyl ester on the growth of C6 glioma cells in vitro and in vivo

Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, has been reported to hold various biochemical responses. In the preliminary study, we found that CAPE inhibited the growth of C6 glioma cells in a dose dependent and time dependent manner as shown by the results of trypan blue dye exclusion assay and cell proliferation assay. In addition, the cell number percentage of the G0/G1 phase increased to 85% after the treatment with 50 microM of CAPE for 24h. After treatment with CAPE (50 microM) for 6h, it demonstrated that the protein level of hyperphosphorylated pRb decreased, and cyclin dependent kinase inhibitors p21, p27, and p16 were marked up-regulated. The association of CDK2 and cyclin E that affects the CDK2 activity decreased. When C6 cells were grown as xenografts in nude mice, treatment with CAPE (1-10mg/kg; ip) induced a significant dose dependent decrease in tumor growth by evaluating tumor volume and tumor weight. Histochemical and immunohistochemical analysis revealed that CAPE treatment significantly reduced the number of mitotic cells and proliferating cell nuclear antigen (PCNA)-positive cells in C6 glioma. These results suggest that CAPE presents an antitumor potential for glioma by inhibiting the growth of tumor cells.     

N-acetyl cysteine and caffeic acid phenethyl ester sensitize astrocytoma cells to Fas-mediated cell death in a redox-dependent manner

In this study, we investigated the role of reactive oxygen species (ROS) in Fas-induced cell death in human astrocytoma cells. Fas activation increased intracellular ROS levels in a NADPH oxidase- and caspase-dependent manner. ROS inhibitors such as N-acetyl cysteine (NAC) and caffeic acid phenethyl ester (CAPE) dramatically sensitized astocytoma cells to Fas-induced loss of mitochondrial transmembrane potential and subsequent cell death, which were abrogated by pretreatment with z-VAD-fmk, a broad-spectrum caspase inhibitor. These results collectively indicate that NAC and CAPE sensitize astrocytoma cells to Fas-induced apoptosis in a redox-dependent manner, suggesting a potential use in the treatment of malignant brain tumors.     

Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation.

We investigated the mechanisms by which caffeic acid phenethyl ester (CAPE), a phenolic antioxidant, inhibited the stimulation of prostaglandin (PG) synthesis in cultured human oral epithelial cells and in an animal model of acute inflammation. Treatment of cells with CAPE (2.5 microg/ml) suppressed phorbol ester (12-O-tetradecanoylphorbol-13-acetate; TPA) and calcium ionophore (A23187)-mediated induction of PGE2 synthesis. This relatively low concentration of CAPE did not affect amounts of cyclooxygenase (COX) enzymes. CAPE nonselectively inhibited the activities of baculovirus-expressed hCOX-1 and hCOX-2 enzymes. TPA- and A23187-stimulated release of arachidonic acid from membrane phospholipids was also suppressed by CAPE (4-8 microg/ml). Higher concentrations of CAPE (10-20 microg/ml) suppressed the induction of COX-2 mRNA and protein mediated by TPA. Transient transfections using human COX-2 promoter deletion constructs were performed; the effects of TPA and CAPE were localized to a 124-bp region of the COX-2 promoter. In the rat carrageenan air pouch model of inflammation, CAPE (10-100 mg/kg) caused dose-dependent suppression of PG synthesis. Amounts of COX-2 in the pouch were markedly suppressed by 100 mg/kg CAPE but were unaffected by indomethacin. These data are important for understanding the anticancer and anti-inflammatory properties of CAPE.     

Anti‐inflammatory effects of caffeic acid phenethyl ester (CAPE), a nuclear factor‐κB inhibitor,on Helicobacter pylori‐induced gastritis in Mongolian gerbils

Nuclear factor‐κB (NF‐κB) plays a major role in host inflammatory responses and carcinogenesis and as such is an important drug target for adjuvant therapy. In this study, we examined the effect of caffeic acid phenethyl ester (CAPE), an NF‐κB inhibitor, on Helicobacter pylori (H. pylori)‐induced NF‐κB activation in cell culture and chronic gastritis in Mongolian gerbils. In AGS gastric cancer cells, CAPE significantly inhibited H. pylori‐stimulated NF‐κB activation and mRNA expression of several inflammatory factors in a dose‐dependent manner, and prevented degradation of IκB‐α and phosphorylation of p65 subunit. To evaluate the effects of CAPE on H. pylori‐induced gastritis, specific pathogen‐free male, 6‐week‐old Mongolian gerbils were intragastrically inoculated with H. pylori, fed diets containing CAPE (0–0.1%) and sacrificed after 12 weeks. Infiltration of neutrophils and mononuclear cells and expression of NF‐κB p50 subunit and phospho‐IκB‐α were significantly suppressed by 0.1% CAPE treatment in the antrum of H. pylori‐infected gerbils. Labeling indices for 5′‐bromo‐2′‐deoxyuridine both in the antrum and corpus and lengths of isolated pyloric glands were also markedly reduced at the highest dose, suggesting a preventive effect of CAPE on epithelial proliferation. Furthermore, in the pyloric mucosa, mRNA expression of inflammatory mediators including tumor necrosis factor‐α, interferon‐γ, interleukin (IL)‐2, IL‐6, KC (IL‐8 homologue), and inducible nitric oxide synthase was significantly reduced. These results suggest that CAPE has inhibitory effects on H. pylori‐induced gastritis in Mongolian gerbils through the suppression of NF‐κB activation, and may thus have potential for prevention and therapy of H. pylori‐associated gastric disorders. © 2009 UICC     

Addition of fusidic acid impregnated bone cement to systemic teicoplanin therapy in the treatment of rat osteomyelitis

We compared the efficacy of the combination of fusidic acid impregnated bone cement and systemic teicoplanin to systemic teicoplanin alone in implant-related osteomyelitis model in the rats. Foreign bodies were implanted into the medullary channels of 30 rat tibias after intramedullary inoculation of methicillin-resistant Staphylococcus aureus. Following proof of induction of osteomyelitis in the rats on the 21st day, a bone cement rod including 1/40 ratio of fusidic acid was inserted into the medullary channel of the tibias in the study group. Teicoplanin was administered i.m. at 20 mg/kg/day for 14 days to both the study and control groups. At the end of the treatment, the tibias were examined macroscopically, microbiologically and histopathologically. The elimination rate with the teicoplanin+fusidic acid combination was 81.8%, while with teicoplanin alone was 55.6% (p=0.33). Although the difference between the two groups was not statistically significant, the combination treatment had a positive effect in eliminating the microorganism.     

Expression of the transformed phenotype induced by diverse acting viral oncogenes mediates sensitivity to growth suppression induced by caffeic Acid phenethyl ester (cape)

Caffeic acid phenethyl ester (CAPE) displays enhanced growth suppressive and toxic effects toward cloned rat embryo fibroblast (CREF) cells transformed by adenovirus type 5 (Ad5) or the Ad5 E1A transforming gene versus untransformed CREF cells (Su et al, Mol Carcinogen 4: 231-242, 1991). The present study was conducted to determine if transformation of CREF cells with additional oncogenes rendered these cells sensitive to the antiproliferative effect of CAPE. Additionally, studies were conducted to determine if reversion of the transformed phenotype could modify CAPE sensitivity. CAPE displayed increased growth suppressive activity toward CREF cells transformed by a number of oncogenes, including Ha-ras, v-src, v-raf, human papillomavirus type 18 (HPV-18) and human papillomavirus type 51 (HPV-51). Employing Ha-ras-transformed CREF (Ha-ras) and Ha-ras-transformed CREF cells overexpressing the Krev-1 suppressor gene (Ha-ras/Krev-1), evidence for a direct relationship between expression of the transformed phenotype and CAPE sensitivity was demonstrated. Ha-ras/Krev-1 cells displaying a suppression of the transformed phenotype exhibited increased resistance to CAPE-induced growth suppression versus Ha-ras cells, whereas Ha-ras/Krev-1 cells escaping transformation-suppression following in vivo growth in nude mice displayed enhanced sensitivity to growth-suppression induced by CAPE. Similarly, mutant Ad5 (H5hr1)-transformed and v-src-transformed CREF cells displaying a stable reversion in transformation also displayed a reduced sensitivity to CAPE versus their transformed counterparts. These observations indicate a direct relationship between expression of the transformed phenotype and CAPE sensitivity. Elucidation of the mechanism by which CAPE selectively inhibits growth of transformed cells should provide important insights into the critical molecular changes mediating expression of the transformed state and could help identify cellular targets for cancer therapy.     

Caffeic acid phenethyl ester profoundly modifies protein synthesis profile in type 5 adenovirus-transformed cloned rat embryo fibroblast cells

Caffeic acid phenethyl ester (CAPE), an active component of propolis from bee hives, exerts a plethora of biological changes in diverse systems. These include antimitogenic, anticarcinogenic, anti-inflammatory and immunomodulatory responses. CAPE directly induces programmed cell death (apoptosis) in type 5 adenovirus (Ad5)-transformed cloned rat embryo fibroblast cells, wt3A. To identify the gene and protein expression changes induced by CAPE in wt3A cells we used a strategy involving in vitro translation of mRNAs followed by high resolution two-dimensional (2D) gel electrophoresis. This approach results in the detection of 745 spots, including 172 displaying differences in expression upon exposure to CAPE. A high proportion of spots show profound changes in spot intensity (42 spots with increased and 27 spots with decreased intensity) following CAPE treatment. These studies provide a basis for comparing these changes to known protein patterns of various cell populations with an ultimate aim of identifying families of polypeptides responsible for the up- and down-regulation of cellular proteins during CAPE-induced apoptosis. Specific newly appearing or completely disappearing spots (52 and 51 molecular species, respectively) will be used to attempt to identify and retrieve their cDNA counterparts from an ordered cDNA library. These approaches represent a novel strategy for cloning genes associated with and potentially mediating apoptosis.     

咖啡酸片治疗肿瘤化疗所致血小板减少症的临床观察

  目的  观察咖啡酸片治疗肿瘤化疗所致血小板减少症（chemotherapy induced thrombocytopenia,CIT）的临床疗效及安全性。   方法  采用自身对照的方法,选取上海交通大学医学院附属瑞金医院等11家三级甲等医院2016年1月22日至2017年1月10日收治的60例肿瘤化疗所致CIT患者。给予咖啡酸片/模拟剂治疗,均为3片/次,3次/d。第1个化疗周期（阴性对照期）于化疗开始第1d给予咖啡酸片模拟剂;第2、3个化疗周期（药物治疗期）需要接受与第1个化疗周期相同方案及剂量的化疗,分别于化疗开始第1d给予咖啡酸片。   结果  药物治疗期最低血小板（platelet,PLT）的升高值显著高于阴性对照期（P < 0.001）;药物治疗期化疗后,PLT恢复后最高值显著高于阴性对照期（P < 0.001）;药物治疗期PLT < 50×109/L的持续天数与阴性对照期无显著性差异,但有缩短趋势（P>0.05）;药物治疗期化疗后PLT恢复至≥75×109/L和≥100×109/L,所需的天数较阴性对照期均明显减少（P < 0.001）;试验期间无患者行PLT输注。   结论  咖啡酸片用于肿瘤化疗所致CIT患者,疗效确切,不良反应较少,具有广泛的临床应用前景。      

DNA damage induced by caffeic acid phenyl ester in the presence of Cu(II) ions: potential mechanism of its anticancer properties

The prooxidant effect of caffeic acid phenyl ester (CAPE) and its structurally analogues on supercoiled pBR322 plasmid DNA strand breakage and calf thymus DNA damage in the presence of Cu(II) ions has been studied. It was found that CAPE exhibit remarkably higher activity in the DNA damage than the ones bearing no ortho-dihydroxyl functionality. Kinetic analysis by UV-visible and fluorescence spectra demonstrates that the formation of CAPE-Cu(II) complexes, the stabilization of oxidative intermediate derived from CAPE and Cu(II)/Cu(I) redox cycles, might be responsible for the DNA damage. This study also reveals a tight correlation between its antioxidant and prooxidant activity. The mechanisms and implications of these observations are discussed.     

Combined Therapy of Teicoplanin and Caffeic Acid Phenethyl Ester (CAPE) in the Treatment of Experimental Mediastinitis in the Rat

Abstract

Post-sternotomy mediastinitis affects 1-3% of patients undergoing cardiac surgery and is lethal in 10-47% of these patients.

We investigated the effect of an antioxidant/anti-inflammatory agent, caffeic acid phenethyl ester (CAPE), in the attenuation of inflammatory response induced by methicillin-resistant Staphylococcus aureus (MRSA) infection in a rat experimental mediastinitis model. Rats, divided into six equal groups, received MRSA precolonized stainless steel wire pieces implanted into their mediastinal spaces. Control group and CAPE control group received saline and CAPE 10 μmol/kg.day^?1 respectively, where Group A received a single dose of teicoplanin 24 mg/kg i.m. for the first day and then 12 mg/kg.day^?1. Group B received teicoplanin as in Group A plus CAPE 10 μmol/kg. day^?1 intra-peritoneally. Group C received teicoplanin 60 mg/kg i.m. for the first day and then 30 mg/kg.day^?1 and Group D received teicoplanin as in Group C plus CAPE 10 μmol/kg.day^?1. By the end of 14 days rats were sacrificed and serum malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), urea and creatinine levels were evaluated. Mediastinal organ tissues were collected for histopathological analysis.

Infection rates in all the drug-treated groups were lower than the control groups (P = 0.002) but statistical significance was attained only between the groups A and D (P = 0.018). In connective tissues and the peribronchial area polymorphonuclear leukocytic (PNL) infiltration in the treatment groups, although becoming very close, did not reach statistical significance (P = 0.053, P = 0.075, respectively). PNL infiltration especially in the peribronchial tissues of the Group B animals was found to be significantly less than the Control and CAPE Control groups with P values of 0.013 and 0.010, respectively. MDA and MPO levels were significantly lower in the treatment groups (P < 0.001 and P < 0.001 respectively). Levels of the degradation products of NO were lower in treatment groups compared to two control groups (P = 0.003, P = 0.005). NO levels in Group D were lowest among all treatment groups (P = 0.001).

It has been demonstrated that although bacterial colonization can be controlled in mediastinitis, the inflammatory response persists. The combination of an antioxidant / anti-inflammatory agent, CAPE, added to standard antibiotic therapy might be effective in the treatment of post-sternotomy mediastinitis due to MRSA.     

Combined treatment strategies in gastrointestinal stromal tumors (GISTs) after imatinib and sunitinib therapy

Resistance to tyrosine-kinase inhibitors remains an open issue in the treatment of patients with gastrointestinal stromal tumors. The complex biology of disease in the multi-resistant setting has led a progressively growing urgency and interest in development combined or integrated therapies. This mini-review outlines the rationale for developing new combined therapeutic approaches, and describes the state of the art of the various potential strategies and the promising research perspectives.