Drug repositioning in chemoprevention of colorectal cancer

Abstract: BackgroundColorectal cancer (CRC) ranks as the third most frequently occurring cancer and the second leading cause of cancer-related deaths worldwide. In response to the high demand for an effective prevention strategy, chemoprevention, using medications to block the pathogenetic pathways of disease, might be an attractive strategy to offer a more effective option at a low cost. Therefore, we aimed to assess the potential beneficial effects of already-approved drugs on the chemoprevention of CRC, especially in high-risk groups. MethodsPapers I, II, and III were population-based cohort studies. By accessing several nationwide Swedish registers, we identified individuals who had ever been previously prescribed melatonin (Paper I), proguanil/atovaquone (Paper II), and selective serotonin reuptake inhibitor (SSRI, Paper III), respectively, and matched them with comparisons who did not use the drugs based on age and sex. The Cox regression model was used to calculate hazard ratios (HRs) and 95% CI confidence intervals (CIs). Paper IV was a nested case-control study exploring the combined effect of SSRIs and aspirin against CRC. We identified CRC cases and randomly matched them to controls conditional on birth year and sex using incidence-density sampling. The conditional logistic regression model was used to calculate odds ratios (ORs) and 95% CIs.ResultsWe found that uses of melatonin (Paper I), proguanil/atovaquone (Paper II), and SSRIs (Paper III) were all associated with a reduced CRC risk, with adjusted HRs and 95% CIs, 0.82 (0.72-0.92), 0.76 (0.62-0.93) and 0.77 (0.70-0.85), respectively. Tests for trends showed significant dose-response correlations (P ConclusionWe identified several potential chemopreventive agents against CRC. Our findings call for further studies to confirm the underlying mechanisms and the plausibility of clinical recommendations.