Alpha-Blockers As Colorectal Cancer Chemopreventive: Findings from a Case?Control Study, Human Cell Cultures, and In Vivo Preclinical Testing
Alpha-Blockers As Colorectal Cancer Chemopreventive: Findings from a Case?Control Study, Human Cell Cultures, and In Vivo Preclinical Testing
复制标题
α-受体阻滞剂作为结直肠癌的化学预防：病例对照研究、人类细胞培养和体内临床前测试的结果
DOI：
10.1158/1940-6207.capr-18-0288
复制
发表时间：
2019
影响因子：
3.3
通讯作者：
Iwamoto Yasuhiko
中科院分区：
文献类型：
--
作者：
Suzuki Nobumi;Niikura Ryota;Ihara Sozaburo;Hikiba Yohko;Kinoshita Hiroto;Higashishima Naoko;Hayakawa Yoku;Yamada Atsuo;Hirata Yoshihiro;Nakata Ryo;Okamoto Makoto;Sano Munetaka;Kushiyama Akifumi;Ichinose Mari;Woods Susan L.;Worthley Daniel;Iwamoto Yasuhiko
进行回顾性病例对照分析，以确定目前使用的候选药物，可以预防结直肠癌，阿司匹林以外。共对37，510例年龄≥20岁的患者进行了评估，以确定通过结肠镜检查诊断为结直肠癌且既往未诊断为结直肠癌、炎症性肠病（IBD）或胃肠道症状的受试者;确定了1，560例通过结肠镜检查诊断为结直肠癌的患者。结直肠癌患者与1，560名年龄，性别，结直肠癌家族史以及在结肠镜检查中未诊断为结直肠癌的共病匹配的对照患者相匹配。比较两组患者的用药史。接下来，选择对照患者更频繁使用的候选药物，并测试其对体外人结直肠癌细胞系和炎症诱导的结直肠癌小鼠模型的影响。确定了可能的结直肠癌预防药物，包括阿司匹林、维生素D、维生素B、维生素C、维生素E、黄嘌呤氧化酶抑制剂、α-受体阻滞剂、血管紧张素受体阻滞剂、那格列奈、益生菌、噻吩并吡啶、叶酸、硝基血管扩张剂、双膦酸盐、钙通道阻滞剂、类固醇和他汀类药物（P< 0.05）。选择α-受体阻滞剂和黄嘌呤氧化酶抑制剂进行进一步研究，因为这些药物以前没有被分析为可能影响结直肠癌预后的因素。在体外，α-受体阻滞剂（α-blocker），而不是非布司他（黄嘌呤氧化酶抑制剂），抑制人结直肠癌细胞的增殖。多沙唑嗪也降低了AOM/DSS小鼠结直肠癌模型中的肿瘤发生。α-受体阻滞剂可以预防结直肠癌。
A retrospective case–controlled analysis was performed to identify drug candidates in the current use that may prevent colorectal cancer, outside of aspirin. A total of 37,510 patients aged ≥20 years were assessed to identify subjects who had been diagnosed with colorectal cancer by colonoscopy without a previous diagnosis of colorectal cancer, inflammatory bowel disease (IBD), or gastrointestinal symptoms; 1,560 patients were identified who were diagnosed with colorectal cancer by colonoscopy. The patients with colorectal cancer were matched with 1,560 age, gender, family history of colorectal cancer and comorbidity-matched control patients who were not diagnosed with colorectal cancer at colonoscopy. The medication histories were compared between the two groups. Next, candidate drugs that were more frequently used by the control patients were selected and their effects on human colorectal cancer cell linesin vitroand an inflammation-induced mouse model of colorectal cancer were tested. Putative colorectal cancer preventative agents were identified, including aspirin, vitamin D, vitamin B, vitamin C, vitamin E, xanthine oxidase inhibitor, alpha-blockers, angiotensin receptor blocker, nateglinide, probiotics, thienopyridine, folic acid, nitrovasodilators, bisphosphonates, calcium channel blockers, steroids, and statins (P< 0.05). Alpha-blockers and xanthine oxidase inhibitors were selected for further study because these agents have not been analyzed previously as factors that may affect colorectal cancer outcomes.In vitrodoxazosin (alpha-blocker), but not febuxostat (xanthine oxidase inhibitor), suppressed the proliferation of human colorectal cancer cells. Doxazosin also decreased tumorigenesis in an AOM/DSS mouse colorectal cancer model. Alpha-blockers may prevent colorectal cancer.