Understanding the molecular mechanisms of cancer prevention by dietary phytochemicals: From experimental models to clinical trials

Table 1 Successful cancer prevention approaches

Cancer prevention approach	Measures undertaken	Demonstration in epidemiological studies/clinical trials	Ref.
Avoid/minimize exposure to known carcinogens/risk factors	Quit cigarettes smoking	Epidemiological study followed up for 40 yr on male British doctors demonstrated decrease in risk	[39-41]
	Decreasing proportion of young smokers	Decrease in mortality due to lung cancer among younger male cohort
	Reduction in number of cigarettes/day or duration of smoking and time since stopping smoking	Epidemiological study - decrease in the rate of lung cancer	[42]
	Ban the production and reduce the usage of carcinogenic aromatic amines	Reduction in bladder cancer among the dye workers	[43]
	Improvement in food preservation techniques	Significant reduction in incidence and mortality due to gastric cancers	[44]
Vaccination	HPV vaccines	Have shown 95%-100% effectiveness in preventing the cervical cancer precursor lesions and in preventing cervical adenocarcinoma in situ. Protection conferred was highly variable in those with prior HPV infection	[45-47]
	Gardasil (HPV 6,11,16,18)
	Cervarix (HPV 16,18)
	HBV vaccines	Rate of HCC decreased in children (6-14 yr)	[48]
	Engerix-B (HBV-DNA)
	Recombivax (HBV surface antigen)
Surgical intervention	Prophylactic resection of high risk organs-bilateral mastectomy and oophorectomy in BRCA1/BRCA2 mutations carriers	Decrease in breast cancer risk and breast and ovarian cancer risk	[49-51]
	Colostomy in FAP patients	Decrease in colorectal cancer risk in patients with APC mutations	[52,53]
Chemoprevention
Non melanoma skin cancer	Topical application of 5-FU, Immiquimod, Diclofenac, PDT with delta-aminolevulinic acid, Ingenolmebutate	Partial or complete clearance of actinic keratosis leading to decrease in cancer	[54-64]
Skin melanoma	Daily or discretionary sunscreen (SPF15+) for 4 yr	Reduction in invasive melanoma in a community based trial	[22]
Breast cancer	Administration of selective estrogen receptor modulating agent(s) (Tamoxifen, Reloxifen)/aromatase inhibitors (Exemestane)	Trials have demonstrated efficacy of these agents in breast cancer prevention, reduction in recurrence and mortality	[25,65,66]
Prostate cancer	Administration of androgen receptor blockers (Finasteride, Dutasteride)	Reduction in prevalence and risk in clinical trials	[67-70]
Colorectal polyps, Adenomas, and cancer	Administration of NSAIDs- Aspirin, Celecoxib, Rofecoxib, Sulindac, DFMO	NSAIDs-mediated reduction in colorectal adenomas	[24,27,51,71-75]
		Significant increase in time to first colorectal cancer occurrence

HPV: Human papillomavirus; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; BRCA: Breast cancer; 5-FU: 5-Fluorouracil; PDT: Photodynamic therapy; NSAIDs: Non-steroidal anti-inflammatory drugs; APC: Adenomatous polyposis coli; DFMO: Difluoromethylornithine.

Table 2 Chemopreventive efficacy of dietary phytochemicals in experimental studies

Compounds	Chemopreventive agent administered (before + during + after carcinogen treatment) route-range of dose	Prevention of carcinogen induced tumors			Pathways modulated		No. of studies reporting protection	Selected ref.
		Target organs	Tumor multiplicity/tumor incidence (#)	Latency period	Cell proliferation/apoptosis	Detoxication pathways
Tocopherols	Diet: 0.3%, 100-4000 mg/kg	Lung, Vagina, Prostate, Colon, Mammary gland	↓(3)/NR	NR	↓(3)/↑(2)	↑(2)	8	[76,77]
Indoles	Diet: 0.25%, 500- 4000 ppm, 0.014 mmol/g, 112 μmol/g, Gavage 50-250 mg/kg BW	Endometrium, Liver, Mammary gland, Lung	↓(5)/↓(2)	↑	↓(4)/↑(3)	↑(3)	14	[31]
Genistein	s.c.: 100-400 mg/mL (100 μL), Gavage: 1-500 mg/kg BW	Mammary gland, Prostate, Seminal vesicles, Buccal pouch, Uterous, Colon, Lung	↓(5)/↓(2)	NR	↓(5)/↑(3)	↑(3)	20	[78]
	Diet: 100-300 mg/kg
Curcumin	Diet: 0.05%-2%, 500-2000 ppm, Topical: 1-100, 3000 nmol	Skin, Digestive system, Intestine1, Mammary gland, Liver, Kidney, Cheek pouch, Esophagus	↓(14)/↓(8)	NR	↓(12)/↑(8)	↑(9)	23	[79-82]
Dially sulphide	i.g.: 150-200 mg/kg BW, Topical: 0.5%-1% (100 μL)	Colon, Kidney, Forestomach, Urinary bladder, Thymus, Lung, Esophagus, Buccal pouch, Skin, Liver, Colon, Kidney	↓(6)/↓(2)	NR	↓(5)/↑(3)	↑(2)	17	[83,84]
Resveratrol	Diet: 60-200 mg/kg	Urinary bladder, Skin, Mammary gland1, Buccal pouch, Tounge, Prostate, Lung, Salivary gland	↓(5)/↓(1)	↑	↓(7)/↑(6)	↑(4)	24	[85-88]
Retinoids	Topical (Oral): 0.5-1.0 mmol/kg BW	Urinary bladder, Skin, Mammary glands1, Buccal puch, Tounge, Prostate, Lung, Salivary gland	↓(6)/↓(1)	↑	-/-	NR	16	[89-91]
	Diet: 150-200 mg/kg
Capsaicin	Diet: 1% capsaicinoids (64.5% capsaicin), Topical (Oral): 10-102 mg/kg BW	Lung, Skin, Tongue, Colon	↓(4)/NR	-	↓(4)/↑(3)	NR	10	[92,93]
Phenethy isothiocyanate	Diet: 5-25 μmol/g, 0.01%-0.1%	Lung, Esophagus, Urinary bladder, Colon	↓(3)/↓(1)	NR	-/-	NR	9	[94-96]
Lycopene	Drinking water: 17 ppm	Prostate, Lung, Colon, Mammary gland1, Buccal pouch, Liver	↓(5)/↓(2)	↑	↓(4)/↑(5)	↑(5)	18	[97]
	Diet: 10-300 mg/kg Gavage: 15-20 mg/kg BW
Green, Black tea polyphenols	Drinking water: 1%-5%, 200-1000 ppm	Liver, Skin, Mammary gland, Lung, Buccal pouch, Colon, Esophagus, Prostate gland	↓(15)/↓(6)	↑	↓(9)/↑(10)	↑(8)	24	[98-104]
	Diet: 0.05%, Topical: 1-200 mg/animal

¹Spontaneous tumors. NR: Not reported; #: No. of studies reported.

Table 3 Evaluation of dietary phytochemicals in clinical trials

Compounds	No. of clinical trials		Chemopreventive agent administered		Target organs	Efficacy	Bioavailability/toxicity issues	Ref.
	Conducted	Results reported	High risk individuals/patients1	Route-dose range
Curcumin	52	3	-/+	Oral: 0.036-8 g daily	Multiple organ sites	+(2)/-(1)	+(1)/-(3)	[105-107]
Genistein	29	7	-/+	Oral: 160-600 mg/d	Breast, urothelial bladder, Mammary gland	NR	+(1)/-(1)	[108,109]
Indoles	4	0	-/+	Oral: 2 serving (½ cup/serving) daily	Prostate, breast, blood	NR	NR/NR	NR
Tocopherols	28	9	+/+	Oral: 50-500 mg/d, 400-1000 IU/d	Prostate, lung	NR	NR/+(2)	[110]
Dially Sulfide	0	0	-/-	NR	NR	NR	NR/NR	NR
Resveratrol	5	2	-/+	Oral: 20-80 mg/d	Colorectal, colon	+(2)	+(1)/-(2)	[32,111]
Retinoids	102	17	+/+	Oral: 1-80 mg/d	Lung, blood, prostate, kidney, skin, blood, head and neck, liver	+(3)/-(7)	NR/+(2)	[112,113]
Capsaicin	2	0	-/+	Oral: 112 mg twice daily for 6 mo, one capsaicin lozenge 4 times daily	Prostate, head and neck	NR	NR/NR	NR
PEITC	9	1	-/+	Oral: Broccoli (300 g) soup four times daily for 5 d, Broccoli seed extract (250 mg), 40 mg PEITC capsules 4 times a day	Lung, oral	-(1)	NR/-(1)	NR
Lycopene	26	24	-/+	Oral: 15-90 mg/d	Prostate	+(1)/-(1)	+(2)/NR	[114,115]
Green tea	85	6	-/+	Oral: 400-2000 mg twice a day, (daily dose is equivalent of 9 cup-of-green tea per day (0.9 g/d GTE, 0.6 g/d EGCG)	Blood, colorectal, prostate, pancreas	+(3)/-3	+(3)/-(3)	[116-118]

¹Study cohort is exclusively of cancer patients. Source: https://clinicaltrials.gov. +: Present; -: Not observed; NR: Not reported; PEITC: Phenethyl isothiocyanate.

Table 4 Properties and biological effects of dietary phytochemicals and approved chemopreventive agents

Dietary phytochemicals	Approved chemopreventive agents
Occurrence
Natural compounds of plant origin	Majority are synthetic compounds while some are biological and/or natural agents
Long History of exposure to humans through food	Human exposure as prescribed drug/vaccine
Easily available and relatively cheaper	Available on prescription and relatively expensive
Properties
Anti-oxidant/polyphenolic in nature, sparingly soluble in water	Widely differing properties and characteristics
Chemopreventive efficacy
Established in experimental models, yet to prove efficacy in clinical trials	Established both in experimental models and clinical trials
Effects-weak to moderate	Effects-moderate to strong
Successful against different classes of carcinogens and at multiple organ sites	May not be successful against different classes of carcinogens and at multiple organ sites
Mechanism(s)
Modulators of redox status and kinase functions, inducer of phase II enzymes	Mechanisms are diverse and may not be related to redox status and/or kinase functions, may not be modulating phase II enzymes
Modulate multiple pathways/targets	Modulation of specific targets/pathways
Specificity
Relatively less specific/non-specific (Pleotropic effects)	Relatively specific to defined agent/exposure and/or molecular pathways
Toxicity
Depends on dose and duration of exposure. Non-toxic at the doses present in food	Depends on dose and duration of exposure