Curcumin (diferuloylmethane) is a dietary phytochemical with low toxicity that exhibits growth-suppressive activity against a variety of cancer cells and possesses certain chemopreventive properties. Curcumin has already been the subject of several clinical trials for use as a treatment in human cancers. Synthetic chemical modifications of curcumin have been studied intensively in an attempt to find a molecule with similar but enhanced properties of curcumin. In this study, a series of novel curcumin analogues were synthesized and screened for anticancer activity. New analogues that exhibit growth-suppressive activity 30 times that of curcumin and other commonly used anticancer drugs were identified. Structurally, the new analogues are symmetrical 1,5-diarylpentadienone whose aromatic rings possess an alkoxy substitution at each of the positions 3 and 5. Analysis of the effects of the analogues on the expression of cancer-related genes usually affected by curcumin indicated that some induced the down-regulation of B-catenin, Ki-ras, cyclin D1, c-Myc, and ErbB-2 at as low as one eighth the concentration at which curcumin normally has an effect. The analogues,
Tumor suppressor p53-dependent apoptosis is thought to be one of the most important tumor-suppressive functions in human tumorigenesis. However, whether the major mechanism underlying the p53-dependent apoptosis is transactivation dependent or independent remains unclear. Using 179 mutant p53s with diverse transcriptional activities for distinct p53-binding sequences in yeast, we evaluated both their sequence-specific transcriptional activities on six p53 target genes and their ability to induce apoptosis in Saos-2 cells. These mutant p53s also represented diversity in their ability to both transactivate target genes and induce apoptosis. We identified 17 mutant p53s with superior ability to induce apoptosis than wild-type p53 that tend to cluster at residues 121 or 290 to 292. There was no significant correlation between the two functional properties on any single target gene examined. Furthermore, the 17 mutant p53s were not classified in a specific cluster by hierarchical cluster analysis on their diverse transcriptional activities, indicating that these mutant p53s were not similar in the transcriptional activity of downstream genes. These results suggested that transactivation-dependent apoptosis does not always play a major role in p53-dependent apoptosis, indirectly supporting the importance role of the transactivation-independent mechanism. (Cancer Res 2005; 65(6): 2108-14)
(1) The mechanisms of tumor suppression are exerted by down-regulation or ablation of a variety of oncogene products including transactivaters such as nuclear factor-kappa B (NF-κB), growth signal transducers such as the Wnt signal molecule, β-catenin, and several growth factors and their receptors, and so on.(2) Curcumin also has anti-invasion, antimetastasis, and antiangiogenesis potential. (3,4) This potential is desirable for new cancer therapeutic agents. β-Catenin is a key molecule of APC (adenomatous polyposis coli)-derived colorectal carcinogenesis (5) that can be phosphorylated as a result of its association with APC, glycogen synthase kinase (GSK)-3β, and then degraded in the ubiquitination pathway. Accumulated β-catenin in the cytoplasm is transferred into the nucleus and acts together with lymphoid enhancer binding factor-1/T-cell-factor family proteins as a transactivator of other oncogenes, including c-myc and cyclin D1.(7-9) The low toxicity of curcumin is also advantageous for clinical use; however, its hydrophobicity, low absorption, and easy degradation are disadvantageous.(1) Recent clinical and preclinical studies of colorectal cancer patients and animals have suggested that curcumin bioavailability is limited. (10)(11)(12) To improve this low bioavailability, we synthesized a series of curcumin analogs and successfully screened an analog named bearing a 30-to 50-fold enhanced tumor suppressive potential against various types of cancers in vitro.(13) The molecular mechanisms of the tumor suppressive effects of GO-Y030 were similar to those of curcumin, including cell cycle arrest, down-regulation of oncogene activities such as NF-κB and Wnt signal transactivation, and induction of caspase 3 activity. The familial adenomatous polyposis (FAP) mouse is a very good model, because it develops adenomas through the same molecular mechanism as in human colorectal carcinogenesis, including the APC tumor suppressor gene. The chemopreventive ability of curcumin was assessed in an FAP model mouse, Min, harboring a truncation mutation at codon 850 with the potential to prevent adenoma formation. (12,14) To examine the bioavailability of synthesized analog and its toxicity, the FAP mouse model was applied. In this study, oral administration of GO-Y030 improved chemopreventive ability in FAP mouse without apparent toxicities in vivo. Materials and MethodsAnimal experiment. Genotyping of Apc 580D/+ mice were carried out by the polymerase chain reaction method as described previously.(15) Apc 580D/+ mice were fed either the basal diet (HFD32; CLEA Japan, Tokyo, Japan) basal diet containing 0.1% (weight/weight) curcumin, or basal diet containing 0.1% or 0.5% GO-Y030. All animal experiments were conducted in accordance with the guidelines set by Tohoku University.Compound. GO-Y030 was synthesized as previously described.Immunohistochemistry. The deparaffinized 4-μm specimens were heated in 1 mM ethylenediaminetetraacetic acid (EDTA)/ 10 mM Tris buffer (pH = 9.0) at 95°C for 40 min. After washing the specimens ...
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