To elucidate the biological significance of activating mutations of BRAF in human malignant tumors, we performed a mutation analysis using 43 cell lines established from tumors that had developed in several kinds of human organs. Because the same V599E point mutation was observed in three of six melanoma cell lines and no such mutations were observed in other types of cancers, we focused further on melanoma, performed mutation analyses of NRAS, KRAS, CTNNB1, and p16/p14(ARF) in these cell lines, and found one NRAS mutation and three p16/p14(ARF) mutations. We further searched for mutations of BRAF and NRAS in 35 primary sporadic melanomas from 35 Japanese patients and detected the V599E BRAF point mutation in only nine (26%) of them. Significant differences in mutation frequency were observed among four histological subtypes; four (50%) of eight superficially spreading melanoma and five (33%) of 15 acral lentiginous melanoma had the mutation, whereas none of 12 other types (six nodular melanoma, five lentigo melanoma, and one mucosal melanoma) had it. The BRAF mutation was observed frequently even in small lesions, indicating that activation of this gene may be one of the early events in the pathogenesis of some melanomas.
(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 ...
BackgroundCurcumin is known to possess many anti-tumor properties such as inhibition of tumor growth and induction of apotosis. However, limited bioavailability of curcumin prevents its clinical application. A synthesized curcumin analog, 1,5-diaryl-3-oxo-1,4-pentadiene such as GO-Y030, has the improved anti-tumor potential in vitro as well as in mouse model of colorectal carcinogenesis.ResultsThese compounds were divided into two groups; one is the higher anti-proliferative group, in which 79.7% of 1,5-diaryl-3-oxo-1,4-pentadienes were clustered. One of the 1,5-diaryl-3-oxo-1,4-pentadiene analogs, GO-Y078 has the most enhanced growth inhibition, and its solubility was improved, compared with curcumin. GO-Y078 inhibits NF-κB transactivation, as well as expression of TP53 and DR5 more effectively than curcumin. In a mouse model, GO-Y078 presented 1.4 fold more survival elongation that was not achieved by curcumin and GO-Y030.ConclusionsThe 1,5-diaryl-3-oxo-1,4-pentadiene analogs can yield good lead compounds for cancer chemotherapy, to overcome low bioavailability of curcumin.
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