Egashira Issei, Takahashi-Yanaga Fumi, Nishida Risa, Arioka Masaki, Igawa Kazunobu, Tomooka Katsuhiko, Nakatsu Yoshimichi, Tsuzuki Teruhisa, Nakabeppu Yusaku, Kitazono Takanari, Sasaguri Toshiyuki
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Medicine and Clinical Science, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cancer Sci. 2017 Jan;108(1):108-115. doi: 10.1111/cas.13106. Epub 2016 Dec 1.
We previously reported that celecoxib, a selective COX-2 inhibitor, strongly inhibited human colon cancer cell proliferation by suppressing the Wnt/β-catenin signaling pathway. 2,5-Dimethylcelecoxib (DM-celecoxib), a celecoxib analog that does not inhibit COX-2, has also been reported to have an antitumor effect. In the present study, we elucidated whether DM-celecoxib inhibits intestinal cancer growth, and its underlying mechanism of action. First, we compared the effect of DM-celecoxib with that of celecoxib on the human colon cancer cell lines HCT-116 and DLD-1. 2,5-Dimethylcelecoxib suppressed cell proliferation and inhibited T-cell factor 7-like 2 expression with almost the same strength as celecoxib. 2,5-Dimethylcelecoxib also inhibited the T-cell factor-dependent transcription activity and suppressed the expression of Wnt/β-catenin target gene products cyclin D1 and survivin. Subsequently, we compared the in vivo effects of celecoxib and DM-celecoxib using the Mutyh mouse model, in which oxidative stress induces multiple intestinal carcinomas. Serum concentrations of orally administered celecoxib and DM-celecoxib elevated to the levels enough to suppress cancer cell proliferation. Repeated treatment with celecoxib and DM-celecoxib markedly reduced the number and size of the carcinomas without showing toxicity. These results suggest that the central mechanism for the anticancer effect of celecoxib derivatives is the suppression of the Wnt/β-catenin signaling pathway but not the inhibition of COX-2, and that DM-celecoxib might be a better lead compound candidate than celecoxib for the development of novel anticancer drugs.
我们之前报道过，选择性COX-2抑制剂塞来昔布可通过抑制Wnt/β-连环蛋白信号通路，强烈抑制人结肠癌细胞增殖。2,5-二甲基塞来昔布（DM-塞来昔布）是一种不抑制COX-2的塞来昔布类似物，也有抗肿瘤作用的报道。在本研究中，我们阐明了DM-塞来昔布是否抑制肠道癌生长及其潜在作用机制。首先，我们比较了DM-塞来昔布与塞来昔布对人结肠癌细胞系HCT-116和DLD-1的作用。2,5-二甲基塞来昔布抑制细胞增殖并抑制T细胞因子7样2表达，其强度与塞来昔布几乎相同。2,5-二甲基塞来昔布还抑制T细胞因子依赖性转录活性，并抑制Wnt/β-连环蛋白靶基因产物细胞周期蛋白D1和生存素的表达。随后，我们使用Mutyh小鼠模型比较了塞来昔布和DM-塞来昔布的体内作用，在该模型中氧化应激会诱发多发性肠道癌。口服塞来昔布和DM-塞来昔布的血清浓度升高到足以抑制癌细胞增殖的水平。塞来昔布和DM-塞来昔布的重复治疗显著减少了癌的数量和大小，且未显示出毒性。这些结果表明，塞来昔布衍生物抗癌作用的核心机制是抑制Wnt/β-连环蛋白信号通路，而非抑制COX-2，并且DM-塞来昔布可能比塞来昔布更适合作为开发新型抗癌药物的先导化合物候选物。
