6-C-(E-phenylethenyl)-naringenin suppresses colorectal cancer growth by inhibiting cyclooxygenase-1.
6-C-(E-phenylethenyl)-naringenin suppresses colorectal cancer growth by inhibiting cyclooxygenase-1.
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DOI：
10.1158/0008-5472.can-13-2245
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发表时间：
2014-01-01
期刊：
影响因子：
11.2
通讯作者：
Dong Z
中科院分区：
文献类型：
--
作者：
Li H;Zhu F;Chen H;Cheng KW;Zykova T;Oi N;Lubet RA;Bode AM;Wang M;Dong Z
最近的临床试验引起了人们对选择性环氧合酶-2（考克斯-2）抑制剂的心血管毒性的关注，并且考克斯-1现在被重新考虑作为化学预防的靶点。我们的目的是确定选择性的考克斯-1抑制是否可以延缓或预防癌症的发展，并阐明其潜在的机制。数据清楚地表明，考克斯-1是维持结肠癌细胞的恶性特征或肿瘤促进剂诱导的肿瘤前细胞转化所必需的。我们还成功地应用配体对接计算方法来鉴定新的选择性考克斯-1抑制剂6-C-（E-苯乙烯基）-柚皮素（在此指定为6 CEPN）。6 CEPN能与考克斯-1结合并特异性抑制其活性。在结直肠癌细胞中，它通过抑制考克斯-1活性而有效抑制锚定非依赖性生长。6CEPN还在28天结肠癌异种移植模型中有效地抑制肿瘤生长，而没有任何明显的全身毒性。综上所述，考克斯-1在人类结直肠癌的发生中起关键作用，并且这种特异性考克斯-1抑制剂作为结直肠癌的潜在预防剂值得进一步研究。
Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors and COX-1 is now being reconsidered as a target for chemoprevention. Our aims were to determine whether selective COX-1 inhibition could delay or prevent cancer development and also clarify the underlying mechanisms. Data clearly showed that COX-1 was required for maintenance of malignant characteristics of colon cancer cells or tumor promoter-induced transformation of pre-neoplastic cells. We also successfully applied a ligand docking computational method to identify a novel selective COX-1 inhibitor, 6-C-(E-phenylethenyl)-naringenin (designated herein as 6CEPN). 6CEPN could bind to COX-1 and specifically inhibited its activity both in vitro and ex vivo. In colorectal cancer cells, it potently suppressed anchorage-independent growth by inhibiting COX-1 activity. 6CEPN also effectively suppressed tumor growth in a 28-day colon cancer xenograft model without any obvious systemic toxicity. Taken together, COX-1 plays a critical role in human colorectal carcinogenesis, and this specific COX-1 inhibitor merits further investigation as a potential preventive agent against colorectal cancer.