tretinoin and caffeic-acid-phenethyl-ester

All-trans retinoic acid (ATRA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL); however, the response is sometimes very slow. Furthermore, relapse and resistance to treatment often occur despite continued treatment with ATRA. Thereafter, combination treatment strategies have been suggested to circumvent these problems. The present study demonstrates that caffeic acid phenethyl ester (CAPE), a major component of honeybee propolis, enhanced ATRA-induced granulocytic differentiation in HL-60, a human promyelocytic cell line. The differentiation was assessed by Wright-Giemsa stain, nitroblue tetrazolium reduction, and membrane differentiation marker CD11b. In addition, CAPE enhanced ATRA-induced cell cycle arrest at the G1 phase by decreasing the association of cdk2-cyclin E complex. Finally, it was demonstrated that CAPE promoted the ATRA-mediated nuclear transcription activation of RARalpha assessed by EMSA assay and enhanced the expression of target genes including RARalpha, C/EBPepsilon, and p21 protein resulting in the differentiation development of leukemia. It is suggested that CAPE possesses the potential to enhance the efficiency of ATRA in the differentiation therapy of APL.

Topics: Antineoplastic Agents; Blotting, Western; Caffeic Acids; CCAAT-Enhancer-Binding Proteins; CD11b Antigen; Cell Cycle; Cell Differentiation; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Drug Synergism; Flow Cytometry; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Lipopolysaccharide Receptors; Phenylethyl Alcohol; Receptors, Retinoic Acid; Receptors, TNF-Related Apoptosis-Inducing Ligand; Retinoic Acid Receptor alpha; Retinoid X Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; Tretinoin

Propolis, obtained from honeybee hives, has been used in Oriental folk medicine as an anti-inflammatory, anti-carcinogenic, and immunomodulatory agent. There is considerable evidence suggesting that angiogenesis and chronic inflammation are codependent. Blockage of angiogenesis results in an anti-inflammatory effect. Ethanol (EEP) and ether extracts of propolis (REP), and caffeic acid phenethyl ester (CAPE), an active component of propolis, were examined for their anti-angiogenic activities using the chick embryo chorioallantoic membrane (CAM), and the calf pulmonary arterial endothelial (CPAE) cell proliferation, assays. The presence of EEP, REP and CAPE inhibited angiogenesis in the CAM assay and the proliferation of CPAE cells. The results suggest that anti-angiogenic activities of EEP, REP and CAPE are also responsible for their anti-inflammatory effect.

Topics: Angiogenesis Inhibitors; Animals; Caffeic Acids; Cattle; Cell Division; Chick Embryo; Chorion; Endothelium, Vascular; Ethanol; Keratolytic Agents; Membranes; Phenylethyl Alcohol; Propolis; Pulmonary Artery; Solvents; Tetrazolium Salts; Thiazoles; Tretinoin

The active component of the honeybee hive product propolis, caffeic acid phenethyl ester (CAPE), has been shown to display increased toxicity toward various oncogene-transformed cell lines in comparison with their untransformed counterparts (Su et al., 4: 231-242, 1991). This observation provides support for the concept that it is the transformed phenotype which is specifically sensitive to CAPE. In the present study, we have determined the effect of CAPE on the growth and antigenic phenotype of a human melanoma cell line, HO-1, and a human glioblastoma multiforme cell line, GBM-18. For comparison, we have also tested the effects of mezerein (MEZ), mycophenolic acid (MPA) and retinoic acid (RA), which can differentially modulate growth, differentiation and the antigenic phenotype in these human tumor cell lines. Growth of both cell lines was suppressed by CAPE in a dose-dependent fashion, with HO-1 cells being more sensitive than GBM-18 cells. The antiproliferative effect of CAPE was enhanced in both cell types if CAPE and MEZ were used in combination. Growth suppression was associated with morphological changes in H0-1 cells, suggesting induction of a more differentiated phenotype. CAPE also differentially modulated the expression of several antigens on the surface of the two tumor cell lines. These results suggest a potential role for CAPE as an antitumor agent, an antigenic modulating agent and possibly a differentiation inducing agent.

Topics: Antigens, Neoplasm; Antineoplastic Agents, Phytogenic; Caffeic Acids; Cell Differentiation; Cell Division; Cytotoxins; Diterpenes; Glioblastoma; Humans; Melanoma; Mycophenolic Acid; Phenotype; Phenylethyl Alcohol; Terpenes; Tretinoin; Tumor Cells, Cultured