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

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.