Table 2.
Various drugs alone and in combination tested for their effects on clinical CRC chemoprevention studies.
| Drugs | Study Design | Mechanism | Main Findings | References |
|---|---|---|---|---|
| Aspirin | Meta-analysis | COX-2 inhibition | There was a dose-dependent reduction in the risk of CR by aspirin. An aspirin dose of 75–100 mg/day reduced the risk by 10%, and 325 mg/day reduced the risk by 35% (Meta-analysis of 45 studies [RR = 0.73, 95% confidence interval (CI) 0.69–0.78]) | [103,104,105,106] |
| Non-aspirin NSAIDS | Meta-analysis | COX-2 inhibition | Data from 23 studies suggested using higher doses of non-aspirin NSAIDs in the general population aged 40 years or older reduced CRC risk, specifically for white women, for distal colon cancer. (Pooled ODDs ratio was 0.74 (0.67–0.81), I2 = 75.9%, p < 0.001.) | [107] |
| Sulindac+ DFMO | RCT | Sulindac inhibits COX-2 DFMO- irreversibly inhibits Ornithine decarboxylase (polyamine synthesis) |
Significant reduction of recurrent adenomas (12 vs. 41%, risk ratio 0.30), advanced adenomas (0.7 vs. 8.5%, risk ratio 0.09), and multiple adenomas (0.7 vs. 13.2%, risk ratio 0.06) | [108,109] |
| DFMO + Aspirin | RCT | Aspirin inhibits COX-2 DFMO inhibits polyamine synthesis Both combined may have a synergistic action. |
After one year of treatment, in the DFMO + aspirin arm vs. placebo, there was a significant reduction in rectal aberrant crypt foci (precursor of rectal carcinoma). (74% vs. 45%, p = 0.020). No statistically significant reduction of colorectal adenomas was observed. | [110] |
| Erlotinib + Sulindac | RCT | Erlotinib is an EGFR inhibitor; sulindac is a COX-2 inhibitor. | In 82 patients of familial adenomatous polyposis, Sulindac + Erlotinib was associated with a 69.4% decrease in those with an intact colorectum compared with placebo (95% CI, 28.8−109.2%; p = 0.009) | [111] |
| Celecoxib | Meta-analysis | Selective COX-2 inhibitor, more specific for inflammation, with fewer GI side effects. Celecoxib has higher cardiovascular mortality | 3 RCTs (involving 4420 patients) and 3 post-trial studies (2159) showed a significant reduction in the incidence of adenoma RR (0.67 [95% CI, 0.62–0.72] compared with placebo). There was an increased risk of cardiovascular mortality with twice dosing 400 mg celecoxib (RR 3.42 [95% CI, 1.56–7.46]). Once-a-day dosing did not show an increased CV risk. (1.01 [95% CI, 0.70–1.46]). | [112] |
| Clopidogrel | Case-control Study | Clopidogrel inhibits platelet aggregation via irreversible inhibition of the P2Y12 receptor | Clopidogrel decreased CRC risk in patients receiving treatment >1 year. (0.65% AOR; 95% CI, 0.55–0.78). Dual antiplatelet therapy (Clopidogrel aspirin) had the same effect as either drug is taken as monotherapy. | [113] |
| Metformin | Meta-analysis | Activates AMPK, inhibits mTOR pathway | Metformin users had a significantly lower incidence. CRC (RR 0.76, CI 0.69–0.84, p < 0.001) compared with non-metformin users. Further analysis on the overall survival of metastatic CRC patients revealed significantly higher survival rates in metformin users (HR 0.77, CI 0.68–0.87, p < 0.001). | [114] |
| UCDA | Cohort Study | Has antioxidant action. Prevents NF-κB and AP1 activity. Inhibits c-Myc |
Chronic liver disease patients with UCDA have a reduced risk of colorectal cancer. UDCA use was associated with a reduced risk of CRC (hazard ratio, 0.60; 95% confidence interval [CI], 0.39–0.92). | [115] |
| Statin | Meta-analysis |
3-HMGCOA reductase inhibitor decreases cholesterol synthesis. Antioxidant activity; shows pro-apoptotic effects on human CRC lines. Anti-inflammatory properties |
14 studies involving 130,994 patients. In terms of post-diagnosis statin uses, the pooled HR of all-cause mortality was 0.86 (95% CI, 0.76–0.98), and the pooled HR of CSM was 0.79 (95%CI, 0.70–0.89) (Cancer-Specific Mortality). | [116,117] |
| Menopausal hormone therapy (combined estrogen-progestin) | Nationwide Cohort Study (Norway) | Estrogens have been proposed to alter bile acid composition, modulate colonic transit. Decrease production of mitogenic insulin-like growth factor |
The current use of postmenopausal hormone therapy was associated with a decreased CRC risk. RR (for combined estrogen-progestin therapy) in oral formulations was 0.86 (95% CI 0.71 to 1.05) | [118] |
| Bisphosphonates | Meta-analysis | Inhibits osteoclastic bone resorption, Anti-apoptotic effect |
Meta-analysis of 34 studies and 4,508,261 participants. There was a significant reduction in the risk of CRC. (RR = 0.89, 95% CI: 0.81–0.98) | [119] |
Abbreviations: RCT, randomized control trial; RR, relative risk; HR, hazard ratio; OR, odds ratio, AOR, adjusted odds ratio; CI, confidence interval; DFMO, difluoromethylornithine; UCDA, ursodeoxycholic acid.