Table 1.

Agents for Chemoprevention of CRC

Agent	Primary Target	Mechanisms	Highest level of clinical evidence	Significant concerns	References
Aspirin and NSAIDs
Aspirin	COX1 and COX2 (irreversible inhibition)	inhibit prostaglandin synthesis, platelet activation, Wnt signaling to beta catenin, and inflammation	RCT	increased risk of bleeding	21
Non-selective NSAIDs (non-aspirin)	COX1 and COX2 (reversible inhibition)	inhibit prostaglandin synthesis, platelet activation, Wnt signaling to beta catenin, and inflammation	RCT	increased risk of bleeding	71
COX-2 inhibitors	COX2 (reversible inhibition)	inhibits prostaglandin synthesis, platelet activation, Wnt signaling to beta catenin, and inflammation	RCT	increased cardiovascular risk	71
Metabolic agents
Metformin	inhibits mitochondrial complex I to prevent production of mitochondrial ATP	activates AMPK, which inhibits the mTOR pathway and reduces cyclin D1 expression and RB phosphorylation	multiple observational studies, one small RCT	lactic acidosis, gastrointestinal side effects (nausea, vomiting, diarrhea)	97–100
Statins	HMG-CoA reductase (reversible inhibition)	disruption of the mevalonate pathway with downstream effects on membrane integrity, cell signaling, protein synthesis, and cell cycle progression	RCTs with cardiovascular effects as the primary endpoint	myalgias, rhabdomyolysis (rare), elevated transaminases (rarely severe)	120, 121
Long-chain omega-3 polyunsaturated fatty acids	components of phospholipids that form cell membranes	anti-proliferative, apoptotic, and anti-angiogenic properties	RCT	unpleasant smelling breath and sweat, nausea, diarrhea	147–149
Vitamins and minerals
Vitamin A	combines with retinol-binding protein, a plasma-specific transport protein	regulates nuclear receptors that suppress tumor formation, induces apoptosis, and enhances immune function	RCT	toxicity can lead to liver damage, joint pain, alopecia, headaches, vomiting, skin desquamation	210, 211
Vitamin C	cofactor in collagen formation and tissue repair	reduces oxidative stress, enhances immune system	RCT	toxicity can lead to nausea, vomiting, diarrhea, headaches	212
Vitamin E	primarily ends up in cell and organelle membranes	inhibits lipid peroxidation in cell membranes, reduces oxidative stress, inhibits carcinogen production	RCT	excessive levels can lead to increased risk of hemorrhagic stroke	213, 214
Beta-carotene	functions as a provitamin A	conflicting evidence of pro- and anti-oxidant properties	RCT	2 large-scale intervention studies have shown an increase in lung cancer among smokers and individuals exposed to asbestos with beta-carotene supplementation.	215, 216–217
Selenium	trace mineral necessary to make selenium-containing proteins	antioxidant effects are most likely due to the antioxidant activity of proteins that contain selenium as an essential component and not from selenium itself	RCT	toxicity can lead to gastrointestinal distress, alopecia, and nail discoloration	218
Folic acid	coenzyme or co-substrate in single-carbon transfers in the synthesis of nucleic acids and amino acid metabolism	proposed mechanism is through effects on DNA replication, repair, and methylation through the one-carbon metabolic pathway	RCT	high levels of folate supplementation could hide vitamin B12 deficiency or accelerate progression of neoplastic lesions	158, 164, 165
Calcium	incorporated into the skeleton	bile acid-binding capacity, direct effect on calcium-sensing receptors on colonocytes	RCT	hypercalcemia can cause nausea, vomiting, constipation, bone pain, kidney stones, confusion, and palpitations	178, 179
Vitamin D	regulates gene transcription via binding to vitamin D receptors located in cell nuclei	inhibits proliferation and angiogenesis, induces differentiation and apoptosis	RCT	dose-limiting hypercalcemic effects	176, 181, 219
New agents
DFMO	ornithine decarboxylase (irreversible inhibition)	inhibits polyamine synthesis which is important for cell survival	RCT (final results pending)	ototoxicity	194
Erlotinib	EGFR tyrosine kinase inhibitor (reversible inhibition)	inhibits EGFR signaling	RCT	gastrointestinal side effects, rash	199
Curcumin	inhibits reactive-oxygen-generating enzymes, protein kinase C, EGFR	anti-inflammatory activity, induces apoptosis	RCT	gastrointestinal side effects at higher doses	220
Guselkumab	monoclonal antibody against IL23 subunit alpha	inhibits IL23 signaling	RCT underway	immunosuppression	203–206
Hydrogen sulfide- and nitric oxide-releasing NSAIDs	COX1 and COX2 (reversible inhibition)	inhibits prostaglandin synthesis, platelet activation, Wnt signaling to beta catenin and inflammation	preclinical studies	decreased risk of gastrointestinal injury	207