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Research Article

Alpha-blockers as colorectal cancer chemopreventatives: findings from a case-control study, human cell cultures, and in vivo preclinical testing.

Nobumi Suzuki, Ryota Niikura, Sozaburo Ihara, Yohko Hikiba, Hiroto Kinoshita, Naoko Higashishima, Yoku Hayakawa, Atsuo Yamada, Yoshihiro Hirata, Ryo Nakata, Makoto Okamoto, Munetaka Sano, Akifumi Kushiyama, Mari Ichinose, Susan L Woods, Daniel Worthley, Yasuhiko Iwamoto and Kazuhiko Koike
Nobumi Suzuki
Division of Gastroenterology, Institute for Adult Diseases Asahi Life Foundation
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  • For correspondence: nsuzuki-ham@umin.ac.jp
Ryota Niikura
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
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Sozaburo Ihara
Division of Gastroenterology, Institute for Adult Diseases Asahi Life Foundation
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Yohko Hikiba
Gastroenterology, Institute for Adult Diseases Asahi Life Foundation
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Hiroto Kinoshita
Gastroenterology, Institute for Adult Diseases Asahi Life Foundation
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Naoko Higashishima
Division of Gastroenterology, Institute for Adult Diseases Asahi Life Foundation
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Yoku Hayakawa
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
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  • ORCID record for Yoku Hayakawa
Atsuo Yamada
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
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Yoshihiro Hirata
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
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Ryo Nakata
Department of Gastroenterology, Japanese Red Cross Medical Center
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Makoto Okamoto
Department of Gastroenterology, JR Tokyo General Hospital
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Munetaka Sano
Department of Gastroenterology, Yaizu City Hospital
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Akifumi Kushiyama
Division of Diabetes and Metabolism, Institute for Adult Diseases Asahi Life Foundation
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Mari Ichinose
School of Medicine, University of Adelaide and South Australian Health and Medical Research Institute
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Susan L Woods
University of Adelaide
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Daniel Worthley
Cancer theme, South Australian Health and Medical Research Institute
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Yasuhiko Iwamoto
Division of Diabetes and Metabolism, Institute for Adult Diseases Asahi Life Foundation
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Kazuhiko Koike
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
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DOI: 10.1158/1940-6207.CAPR-18-0288
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Abstract

A retrospective case-controlled analysis was performed to identify drug candidates in the current use that may prevent colorectal cancer (CRC), outside of aspirin. A total of 37,510 patients aged ≥20 years were assessed to identify subjects who had been diagnosed with CRC by colonoscopy without a previous diagnosis of CRC, inflammatory bowel disease (IBD), or gastrointestinal symptoms; 1560 patients were identified who were diagnosed with CRC by colonoscopy. The CRC patients were matched with 1560 age-, gender-, family history of CRC-and comorbidity-matched control patients who were not diagnosed with CRC 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 CRC cell lines in vitro and an inflammation-induced mouse model of CRC were tested. Putative CRC preventative agents were identified, including aspirin, vitamin D, vitamin B, vitamin C, vitamin E, xanthine oxidase inhibitor, alpha- blockers, angiotensin receptor blocker (ARB), nateglinide, probiotics, thienopyridine, folic acid, nitrovasodilators, bisphosphonates, Ca-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 CRC outcomes. In vitro doxazosin (alpha-blocker), but not febuxostat (xanthine oxidase inhibitor), suppressed the proliferation of human CRC cells. Doxazosin also decreased tumorigenesis in an AOM/DSS mouse colorectal cancer model. Alpha-blockers may prevent CRC.

  • Received August 13, 2018.
  • Revision received December 17, 2018.
  • Accepted January 18, 2019.
  • Copyright ©2019, American Association for Cancer Research.

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Published OnlineFirst January 30, 2019
doi: 10.1158/1940-6207.CAPR-18-0288

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Alpha-blockers as colorectal cancer chemopreventatives: findings from a case-control study, human cell cultures, and in vivo preclinical testing.
Nobumi Suzuki, Ryota Niikura, Sozaburo Ihara, Yohko Hikiba, Hiroto Kinoshita, Naoko Higashishima, Yoku Hayakawa, Atsuo Yamada, Yoshihiro Hirata, Ryo Nakata, Makoto Okamoto, Munetaka Sano, Akifumi Kushiyama, Mari Ichinose, Susan L Woods, Daniel Worthley, Yasuhiko Iwamoto and Kazuhiko Koike
Cancer Prev Res January 30 2019 DOI: 10.1158/1940-6207.CAPR-18-0288

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Alpha-blockers as colorectal cancer chemopreventatives: findings from a case-control study, human cell cultures, and in vivo preclinical testing.
Nobumi Suzuki, Ryota Niikura, Sozaburo Ihara, Yohko Hikiba, Hiroto Kinoshita, Naoko Higashishima, Yoku Hayakawa, Atsuo Yamada, Yoshihiro Hirata, Ryo Nakata, Makoto Okamoto, Munetaka Sano, Akifumi Kushiyama, Mari Ichinose, Susan L Woods, Daniel Worthley, Yasuhiko Iwamoto and Kazuhiko Koike
Cancer Prev Res January 30 2019 DOI: 10.1158/1940-6207.CAPR-18-0288
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eISSN: 1940-6215
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