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. 2023 Apr 20;24(8):7597. doi: 10.3390/ijms24087597

Table 1.

Chemopreventive agents for CRC. Abbreviations: 5-ASAs, 5-aminosalicylates; ACF, aberrant crypt foci; AIM2, Absent In Melanoma 2; AMPK, 5-adenosine monophosphate-activated protein kinase; AOM, azoxymethane; APACC, Association pour la Prévention par l’Aspirine du Cancer Colorectal; APC, Adenoma Prevention with Celecoxib; APPROVe, Anomatous Polyp Prevention on Vioxx; ASCOLT, Aspirin for Dukes C and High-Risk Dukes B Colorectal Cancers; ASPIRED, Aspirin Intervention for the Reduction of CRC Risk; ATP, adenosine 5′-triphosphate; CALGB, Cancer and Leukemia Group B; CAPP, Colorectal Adenoma/Carcinoma Prevention Program; CCFR, Colon Cancer Family Registry; COX, cyclooxygenase; CPS II, Cancer Prevention Study II; CRC, colorectal cancer; DFMO, difluoromethylornithine; EB3IV, recombinant protein ERBB3 residues 269–396; EBX, extracellular amino acid residues 299–323 of ERBB3; EGFR, epidermal growth factor receptor; EPA, eicosapentanoic acid; ERBB3, Erb-B2 Receptor Tyrosine Kinase 3; FAP, familial adenomatous polyposis; FSP, frameshift peptides GAd, Great Ape Adenovirus; HMG-CoA, hydroxy-β-methylglutaryl-CoA; HPFS, Health Professionals Follow-up Study; KLH, keyhole limpet hemocyanin; IL-23, interleukin-23; HT001, protein asteroid homolog 1; MUC-1, mucin-1; MVA, Modified Vaccinia virus Ankara; N.A., not applicable; NA-NSAIDs, non-aspirin non-steroidal anti-inflammatory drugs; NHS, Nurses’ Health Study; PHS, Physicians’ Health Study; ppm, parts per million; Pre-Sap, Prevention of Colorectal Sporadic Adenomatous Polyps; PUFA, polyunsaturated fatty acid; RB, retinoblastoma; RCT, randomized controlled trial; seAFOod, Systematic Evaluation of Aspirin and Fish Oil; TAA, tumor-associated antigen; TF1B, TATA-Box Binding Protein Associated Factor, RNA Polymerase I Subunit B; UDCA, ursodeoxycholic acid; ukCAP, United Kingdom Colorectal Adenoma Prevention; USPSTF, US Preventive Services Task Force; WHS, Women’s Health Study.

Agent Primary
Target		 Mechanism Endpoint Study or Trial
(Years)		 Participants (n) Age of
Participants		 CRC Risk Level Dose Median Time of Follow-Up Results Ref
Anti-inflammatory agents
Aspirin COX-1 and COX-2 (irreversible inhibition) Inhibits prostaglandin synthesis and the β-catenin WNT pathway ACF In vivo studies AOM-treated rats N.A. N.A. 0.2–0.6% N.A. Reduced ACF number and size [35,36]
Adenoma CALGB
(1993–2000)		 Individuals with prior CRC (517) 30–80 years High 325 mg daily 13 months Reduced adenoma risk [38]
CAPP1
(1993–2005)		 FAP patients (133) 10–21 years High 600 mg twice daily After 1 year and then annually Reduced adenoma largest size [41]
AFPPS
(1994–1998)		 Individuals with prior adenomas (1121) 21–80 years Moderate 81 mg or 325 mg daily 3 years Low dose but not high dose reduced the risk of adenoma recurrence [37]
ukCAP
(1997–2005)		 Individuals with prior adenomas
(945)		 Younger than 75 years Moderate 300 mg daily 3 years Reduced adenoma recurrence risk [39]
APACC
(1997–2001)		 Individuals with prior adenomas
(272)		 18–75 years Moderate 160 mg or 300 mg daily 1 and 4 years Reduced adenoma risk after 1 year, but not after 4 years [40,42]
seAFOod
(2010–2017)		 Individuals with prior adenomas
(709)		 55–73 years Moderate 300 mg daily 1 year Reduced number of conventional and serrated adenomas in the right colon at secondary analysis [43]
Cross-sectional studies
(2011–2014)		 General population divided into smokers and non-smokers and people with CRC family history (2918) 45–65 years Average and moderate 81 mg 30 months Reduced adenoma risk only in non-smoker users [45]
CRC NHS
(1980–2000)		 General population (82,911 female) 30–55 years Average 325 mg 2 times per week Every 2 years Reduced CRC risk [46]
PHS
(1982–1995)		 General population (22,071 male) 40–84 years Average 325 mg on alternate days 5–12 years No reduced CRC incidence [47]
CPS II
(1982–1988)		 General population
(662,424)		 57 years (mean) Average 100 mg on alternate days 10–18 years Reduced CRC risk [48]
HPFS
(1986–1990)		 General population (47,900 male) 40–75 years Average 100 mg 2 times per week 2–4 years Reduced CRC risk and metastatic CRC [49,50]
WHS
(1993–2004)		 General population (39,876 female) 45 years or older Average 100 mg on alternate days 1-10-18 years Reduced CRC incidence only after 10 or 18 years of follow-up [51,52]
CCFR
(1997–2012)		 Lynch syndrome patients
(1858)		 43 years (mean) High Twice a week Not reported Reduced CRC risk [53]
CAPP2
(2001–2008)		 Lynch syndrome patients
(861)		 45 years (mean) High 600 mg daily 2–10 years No reduced CRC risk after two years of follow-up, a strong reduction in CRC risk at 10 years [54,55]
USPSTF
(2004–2015)		 General population and individuals with prior adenomas 40–79 years Average and moderate 75 mg daily or on alternate days 10–20 years Reduced CRC risk and mortality [56,57]
J-CAPP
(2007–2012)		 Individuals with prior adenomas (311) 40–70 years Moderate 100 mg daily 2 years Reduced CRC risk in the non-smoker population [58]
ASCOLT
(2008-ongoing)		 Dukes’ B and C CRC (1587) 18 years and older High 200 mg daily Every 3 months for 3 years + every 6 months for another 2 years Final results pending [59]
Pooled analysis derived from 4 RCTs and 1 study of different doses of aspirin (2010) General population (13,500) 45–69 years Average 75 mg or 300 mg daily 20 years Reduced CRC risk and mortality [60]
ASPIRED
(2010-ongoing)		 Individuals with prior adenomas (180) 50–69 years Moderate 81 mg or 325 mg daily Every 6 months Final results pending [61]
CAPP3
(2014–2019)		 Lynch syndrome patients
(1500)		 Not reported High 100 mg or 300 mg or 600 mg daily 5 years Final results pending [62]
J-FAPP
(2015–2017)		 FAP patients
(311)		 40–70 years High 100 mg and/or mesalazine daily 8 months Reduced adenoma and CRC risk [58]
NA-NSAIDs COX-1 and COX-2 (reversible inhibition) Inhibit prostaglandin synthesis and WNT signaling pathway ACF Sulindac General population and individuals with a CRC family history
(304)		 55–75 years Average and moderate 150 mg 2 months and 1 year Reduced ACF number [88]
Adenoma Sulindac FAP patients
(46)		 14–46 years High 300 mg daily 1 year Reduced adenoma risk [89,90,91]
Double-blind, placebo-controlled study (celecoxib)
(1996–1998)		 FAP patients (77) 18–65 years High 100 mg or 400 mg twice daily 6 months Reduced adenoma risk [93]
Double-blind, placebo-controlled study
(rofecoxib)		 FAP patients (21) Not reported High 25 mg 3-6-9 months Reduced adenoma risk [94]
Nested case-control study (rofecoxib and celecoxib) General population (3477) 65 years or older Average Not reported 3 months Reduced adenoma risk [95]
APC trial
(1999–2002)		 Individuals with prior adenomas (2035) 31–88 years Moderate Celecoxib 200 mg or 400 mg twice daily 3–5 years Reduced adenoma risk [96,97]
Pre-Sap
(2001–2005)		 Individuals with prior adenomas (1561) 30 years or older Moderate Celecoxib 400 mg daily 1–3 years Reduced adenoma risk [99]
APPROVe
(2001–2004)		 Individuals with prior adenomas (2586) 40–96 years Moderate Rofecoxib 25 mg daily 1–3 years Reduced adenoma risk [101]
5-ASAs Derivatives of aspirin Inhibit prostaglandin synthesis Adenoma and CRC Observational studies
(1972–2002)		 Ulcerative colitis patients Not reported High Mesalamine >1.2 g/day
Sulfasalazine >2.4 g/day		 10-20-30 years Reduced adenoma and CRC risk [106,107,108]
UDCA Secondary bile acids Disruption of the balance between colorectal crypt cell proliferation, differentiation, and apoptosis ACF In vivo studies AOM-treated Fisher male rats (344) N.A. N.A. UDCA 0.2% or 0.4% for 2 weeks 28 weeks Reduced ACF number [109,110]
Adenoma and CRC Phase III clinical trial Individuals with prior adenomas and ulcerative colitis patients
(1285)		 40–80 years Moderate and high 300 mg 3 years Reduced adenoma and CRC risk [111]
Cross-sectional study Ulcerative colitis and primary sclerosing cholangitis patients
(59)		 Not reported High 9.9 mg/kg daily 3 years Reduced adenoma and CRC risk [112,113]
Metabolic agents
Metformin Inhibits mitochondrial complex I to prevent the production of mitochondrial ATP Activates AMPK, reduces cyclin D1 expression and RB phosphorylation ACF and adenoma In vivo studies AOM-BALB/c mice N.A. N.A. 250 mg/kg daily 6 weeks for ACF and 32 weeks for adenomas Reduced ACF and adenoma risk [120]
Adenoma In vivo studies APCMin/+ mice N.A. N.A. 250 mg/kg N.A. Reduced number of intestinal polyps larger than 2 mm [121]
ACF, adenoma Short-term randomized study Non-diabetic patients
(26)		 65–75 years Average 250 mg daily 1 month Reduced ACF and adenoma risk [122]
ACF RCT Non-diabetic patients
(60)		 Not reported Average 250 mg and/or aspirin 100 mg daily 8 weeks Final results pending [123]
Adenoma Multicenter double-blind, placebo-controlled, randomized phase 3 trial
(2011–2014)		 Non-diabetic patients
(498)		 20 years or older Average 250 mg daily 1 year Reduced prevalence and number of metachronous adenomas or polyps after polypectomy [124]
Adenoma and CRC Case-control studies and RCT (2008–2016) Non-diabetic and diabetic patients, individuals with prior adenomas and CRC
(8726)		 40–89 years Average, moderate, and high ≥250 mg daily 4–15 years Reduced adenoma and CRC risk [125]
Epidemiology studies Non-diabetic and diabetic patients 20–80 years Average and high 250 mg or 500 mg daily 1–3 years Conflicting results [126,127,128,129,130,131,132,133,134,135,136,137]
CRC Retrospective cohort study Diabetic patients (60,520) 40 years or older High 750–4000 mg daily 5 years Reduced CRC risk [138]
Statins HMG-CoA reductase (reversible inhibition) Disruption of the mevalonate pathway Adenoma and CRC In vivo studies APCMin/+ mice 6-week-old N.A. Pitavastatin at doses of 20 and 40 ppm 14 weeks Reduced adenomas in a dose-dependent way [142]
In vivo studies AOM-treated F344 rats 5-week-old N.A. Atorvastatin 100–200 ppm and/or sulindac 100 ppm or naproxen 150 ppm 45 weeks Reduced CRC risk [143]
In vivo studies APCMin/+ mice 6-week-old N.A. Atorvastatin 100 ppm and/or celecoxib 300 ppm 80 days Reduced adenoma and CRC risk [144]
Adenoma Review of endoscopy and pathology databases Individuals with prior adenomas
(2626)		 63 years (mean) Moderate Not reported 3–5 years Reduced adenoma risk [145]
Secondary analysis of data from three large colorectal adenoma chemoprevention trials General population (2915) Not reported Average Not reported Not reported No reduced adenoma risk [146]
CRC Molecular Epidemiology of Colorectal Cancer Study
(1998–2004)		 Individuals with prior CRC
(3968)		 58–80 years High Not reported 5 years Reduced CRC risk [147]
Double-blind trial Patients with myocardial infarction who had plasma total cholesterol levels below 240 mg/dL and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg/dL (4159) 50–70 years Moderate Pravastatin 40 mg daily 5 years Reduced CRC risk [148]
Survival study Patients with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L
(4444)		 35–70 years Moderate Simvastatin 20–40 mg daily 5 years Reduced CRC risk [149]
Systematic review and meta-analysis General population 40–80 years Average Not reported 3–6 years Conflicting results [150]
Long-Chain Omega-3 PUFAs Components of phospholipids that form cell membranes Anti-proliferative, apoptotic, and anti-angiogenic properties ACF In vivo studies Wistar rats N.A. N.A. EPA 18.7%; DHA 8% 48 h Reduced ACF number [158]
ACF, adenoma, and CRC In vivo studies APCMin/+ mice, AOM-treated mice, xenograft mice N.A. N.A. EPA 4–16%; DHA 0.75–6% 1 day-32 weeks Reduced ACF number, adenoma, and CRC risk [159]
Adenoma Prospective study
(2006–2007)		 FAP patients (55) 18 years or older High EPA 500 mg twice daily 6 months Reduced adenoma risk [161]
seAFOod
(2010–2017)		 Individuals with prior adenomas
(709)		 55–73 years High EPA 2 g daily 1 year Reduced number of conventional and left-sided adenomas at secondary analysis [43]
CRC Prospective study
(2000–2008)		 General population (68,109) 50–76 years Average Fish oil more than 4 days per week 3 years Reduced CRC risk [162]
RCTs
(2001–2011)		 General population, FAP patients 40–75 years Average and high EPA 0.09 vs. 0.03 g daily
DHA 0.18 vs. 0.08 g daily		 3–22 years Conflicting results [163,164,165]
Folic acid Coenzyme in single transfers in the synthesis of nucleic acid and amino acid metabolism Maintaining normal DNA methylation required for synthesis and repair ACF and CRC In vivo studies AOM-treated rats (159) 6-week old N.A. 0, 2, 5, or 8 mg/kg 34 weeks Conflicting results [166,171]
Adenoma and CRC Epidemiology studies General population Not reported Average 100 μg or 600 μg daily Not reported Reduced CRC risk [172,173,174]
Adenoma RCT General population, individuals with prior adenoma 65 years (mean) Average and high 0.5 to 2.5 mg daily 36–88 months No reduced adenoma risk [175]
CRC NHS
(1980–1994)		 General population
(88,756 female)		 30–55 years Average 200 μg or 400 μg daily Every 2 years Reduced risk of CRC [176]
Canadian National Breast Screening Study General population (5681) Not reported Average 200 μg or 400 μg daily 10 years Reduced risk of CRC [177]
Case-control studies Ulcerative colitis patients Not reported High 0.4–1.0 mg daily Not reported Reduced risk of CRC [178,179]
Antioxidant agents
Selenium Trace minerals required to make selenium-containing proteins Antioxidant properties Adenoma and CRC RCT General population 62 years (mean) Average 200 μg daily 6–12 years Conflicting results [187,188,189]
Vitamin A Combines with retinol-binding protein Regulates nuclear receptors that are involved in tumor formation CRC Observational studies General population 34–80 years Average 1 μg daily 8–10 years Conflicting results [192,193]
Vitamin C Cofactor in collagen formation and tissue repair Reduces oxidative stress CRC RCT General population 40–80 years Average 75 mg or 250 mg or 500 mg daily 5–9 years No reduced CRC risk [188,192,193]
Vitamin E Primarily ends up in cell and organelle membranes Inhibits lipid peroxidation in membranes CRC RCT General population Not reported Average 30 mg or 50 mg or 600 mg daily 6–12 years No reduced CRC risk [187,188,189,192,193,194,195]
β-carotene Functions as a provitamin A Antioxidant properties CRC RCT General population 55 years (mean) Average 20 mg or 30 mg daily 2–12 years No reduced CRC risk [187,188,189,196,197]
Curcumin Inhibits reactive oxygen-generating enzymes Antioxidant properties Adenoma Prospective study FAP patients
(5)		 Not reported High Curcumin 480 mg and quercetin 20 mg orally 3 times a day Every 3 months Reduced adenoma risk [199]
RCT
(2011-2016)		 FAP patients
(44)		 18–85 years High 3000 mg daily 1 year No reduced adenoma risk [200]
Minerals and vitamin D
Magnesium Involved in metabolism, insulin resistance, and inflammation Important for DNA synthesis and repair ACF and CRC In vivo studies Methylazoxymethanol acetate-treated male F344 rats N.A. N.A. 250 ppm or 500 ppm 1000 ppm 4-6-8 weeks Reduced ACF and CRC risk [202,203]
CRC In vivo studies Methylazoxymethanol acetate-treated male F344 rats N.A. N.A. 500 ppm or 1000 ppm 227 days Reduced CRC risk [203]
CRC Prospective studies
(2005–2012)		 General population (338,979) 40–75 years Average 50 mg daily 8–28 years Reduced CRC risk [204]
Adenoma Case-control studies General population, individuals with a CRC family history 18–75 years Average and moderate 100 mg daily Not reported Reduced adenoma risk [205]
Adenoma and CRC Epidemiologic and prospective studies General population (1,236,004) Not reported Average 300–400 mg daily Not reported Reduced adenoma and CRC risk [206]
Calcium Incorporated into the skeleton Bile acid-binding capacity CRC In vivo studies 1,2-Dimethylhydrazine (DMH)-treated Slac mice
(80)		 N.A. N.A. 1.24–3.0% 24 weeks Reduced CRC risk [210]
Adenoma Calcium Polyp Prevention Study Group RCT Individuals with prior adenomas (930) 61 years (mean) Moderate 3 g daily 1-4-9 years Reduced advanced adenoma recurrence risk [211,212,213]
The European Cancer Prevention Intervention Study Individuals with prior adenomas (665) 35–75 years Moderate 2 g daily 3 years No significant effect on adenoma risk [214]
Systematic review and meta-analysis of RCTs
(2010)		 General population, individuals with prior adenomas, FAP patients 16–80 years Average, moderate, and high 500 mg−2 g−3 g daily 6 months–7 years No positive results for average- and high-risk populations, reduced adenoma risk in individuals with a history of adenomas [215]
CRC Cancer Prevention Study II Nutrition Cohort
(1992-1993)		 General population (1,277,499) 50–74 years Average 500 mg daily 5 years Reduced CRC risk [216]
Prospective study
(2000)		 General population (61,463) 53 years (mean) Average 900 mg daily 12 years Reduced CRC risk [217]
NHS and HPFS General population (135,342) 30–75 years Average 500–1250 mg daily 10–16 years Reduced distal colon cancer risk [218]
Prospective study General population (34,702) Not reported Average Not reported 9 years Reduced rectal cancer risk [219]
WHS General population (36,282 female) 50–79 years Average Calcium carbonate 500 mg and vitamin D 200 IU twice daily 7 years No reduced CRC risk [220]
Vitamin D Regulates gene transcription by binding vitamin D receptors Inhibits proliferation and angiogenesis Adenoma, CRC, and rectal cancer RCT General population, individuals with prior adenomas 50–79 years Average and moderate 400 IU daily 7 years Conflicting results [220,225,226]
CRC RCT General population (25,871) 50 years or older Average Vitamin D 2000 IU and omega-3 fatty acids 1 g daily 5 years No reduced CRC risk [227,228]
Hormone replacement therapy
Hormones Increase the production of insulin-like growth factor-I or secondary bile acids Inhibit proliferation and promote cell cycle arrest and apoptosis Adenoma Prospective studies Individuals with prior adenomas
(411)		 30–74 years Moderate Not reported Not reported Reduced adenoma risk [232,233,234,235]
CRC The Molecular Epidemiology of Colorectal Cancer Study
(1998–2006)		 Individuals with prior CRC
(1234)		 60 years or older High Not reported 5 years Reduced CRC risk [236,237,238,239]
Women’s Health Initiative (WHI)
RCT		 General population (postmenopausal status)
(10,739)		 50–79 years Average Conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg daily 7 years No reduced CRC risk [240,241,242]
Dietary products
Fibers Involved in the metabolism and catabolism of bioactive food components Decrease the exposure of colonic cells to carcinogens CRC RCT General population 25–76 years Average 90 g daily increments 6–16 years Reduced CRC risk [246,247,248,249,250]
Fruits and vegetables Involved in the metabolism and catabolism of bioactive food components Decrease the exposure of colonic cells to carcinogens CRC RCT General population 34–82 years Average 100 g daily increments Not reported Reduced CRC risk [163,246,248,251,252,253,254,255,256]
Vaccines
FSP-based vaccines TAF1B(−1), HT001(−1), and AIM2(−1) Development of humoral and T-cell responses against FSPs CRC Phase I/IIa clinical trial
(2011–2015)		 Lynch syndrome
(22)		 55 years (mean) High 3 cycles of subcutaneous vaccinations mixed with Montanide ISA-51 VG 6 months Enhanced immune response against FSP peptides [259]
Nous 209 viral-vectored vaccine 209 FSPs Neoantigen-based vaccine for the treatment of MSI tumors Immunogenic response In vivo studies CB6F1 mice 6-week-old N.A. GAd-209-FSP and MVA-209-FSP were administered i.m. at the dosage of 4 × 108 vp and 4 × 107 ifu, respectively 3 weeks CD8 and CD4 T-cell responses [260]
CRC Phase I/II clinical trial
(2019–2025)		 Individuals with prior CRC
(34)		 18 years or older High GAd-209-FSP low dose;
MVA-209-FSP low dose; GAd-209-FSP high dose; MVA-209-FSP high dose; GAd20-209-FSP; RP2D; MVA-209-FSP, RP2D		 Up to 110 weeks Final results pending [261]
Phase Ib/II clinical trial
(2021–2025)		 Lynch syndrome patients
(45)		 18 years or older High GAd-209-FSP and MVA-209-FSP Every 12 months Final results pending [262]
Synthetic peptide ERBB3 Development of humoral and cellular immunity against FSPs Adenoma In vivo studies APCMin/+ mice 3-week-old N.A. 100 mg of EBX peptide, EB3IV, or KLH in 100 mL of a 50/50 mixture of antigen and CFA 3 months Reduced recurrent adenomas [263]
TAA vaccine MUC-1-derived peptides Anti-MUC-1 IgG response Adenoma Phase II clinical trial—RCT
(2008–2013)		 Individuals with prior adenomas 40–70 years Moderate 100 µg MUC1 + Hiltonol®at week 0, 2, 10, and 52 54 weeks Reduced recurrent adenomas [264,265]
Target therapy
DFMO Ornithine decarboxylase (irreversible inhibition) Inhibits polyamine synthesis Adenoma RCT Individuals with prior adenomas
(375)		 40–80 years Average and high DFMO 500 mg daily and/or sulindac 150 mg 36 months Reduced recurrent adenomas [268]
RCT FAP patients
(171)		 18 years or older High DFMO 750 mg and/or sulindac150 mg 48 months Conflicting results [269]
RCT FAP patients
(112)		 38 years (mean) High DFMO 250 mg and/or celecoxib 400 mg 6 months Modest reduction in adenoma risk [270]
Erlotinib EGFR tyrosine kinase inhibitor (reversible inhibition) Inhibits EGFR signaling Adenoma RCT
(2010–2014)		 FAP patients
(92)		 41 years (mean) High Erlotinib 75 mg daily and/or sulindac 150 mg twice daily 6 months Reduced recurrent adenomas [277,278]
Guselkumab Monoclonal antibody against IL-23 subunit alpha Inhibits IL-23 signaling Adenoma RCT FAP patients Not reported High Not reported Not reported Final results pending [280]