Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

Table 1 In vitro effects of natural terpenoids on various liver cancer cells

Terpenoids	Compounds	Cellular effects	Mechanisms	Conc.	Ref.
Monoterpenes	Geraniol	Inhibited the growth of HepG2 cells	↓HMG-CoA reductase	50-400 μmol/L	Polo et al[68]
Diterpenes	Andrographolide	Inhibited the growth of Hep3B cells	↑apoptosis; ↑ MAPKs; ↑pJNK; ↑ERK1/2	3-100 μmol/L	Ji et al[69]
	Excisanin A	Decreased viability of Hep3B cells	↑apoptosis; ↓pAKT	1-32 μmol/L	Deng et al[70]
	Gnidimacrin	Demonstrated tumor inhibition in PKC βII-transfected HLE cells	⊥G2; ↓cdc2; ↑p21WAF1/CIP1	0.00001-0.1 μg/mL	Yoshida et al[71]
	Oridonin	Promoted cytotoxicity in HepG2 cells	↑apoptosis; ↑ROS; ↑p53; ↑p38; ↓ΔΨm; ↑cyt. c; ↑caspase-3, -9	10-50 μmol/L	Huang et al[72]
Triterpenes	Actein	Inhibited the growth of p53-positive HepG2 cells		27 μg/mL [IC50]	Einbond et al[75]
	Ardisiacrispin (A+B)	Exhibited cytotoxicity against Bel-7402 cells	↑apoptosis; ↓proliferation; microtubule disassembly	1-10 μg/mL	Li et al[76]
	Astragaloside IV	Decreased colonogenic survival and inhibited anchorage-independent growth of HepG2 cells	↓Vav3.1; ↑HSP70; ↑HSPA1A; ↑HSPA8; ↑BiP/GRP78	150-200 μg/mL	Qi et al[78]
	Asiatic acid	Decreased viability of HepG2 cells	↑apoptosis; ↑Ca2+; ↑p53	10-100 μmol/L	Lee et al[79]
	Betulinic acid	Displayed cytotoxicity against HUH6, HepT1 and HepT3 cells	↑apoptosis; ↑caspase 3; ↓PI3K/AKT; ↓GLI1; ↓PTCH1; ↓IGF2	1-50 μg/mL	Eichenmüller et al[80]
		Failed to induce apoptosis against HepG2 cells	↑survivin; ↑Bcl-2	0.1-50 μg/mL	Eichenmüller et al[80]
	Cucurbitacin B	Decreased the viability of HepG2 cells	↑apoptosis; ↓Bcl-2; ↓pSTAT3	10 nmol/L-10 μmol/L	Zhang et al[83]
		Exhibited growth inhibitory effects on Bel-7402 cells	↑apoptosis; ⊥S; ↓cyclin D1; ↓cdc2; ↓c-Raf; ↑ERK 1/2	0.01-1000 μmol/L	Chan et al[84]
	Cucurbitacin D	Suppressed the growth of Hep3b cells	↑apoptosis; ↑caspase-3; ↑pJNK	0-10 μmol/L	Takahashi et al[85]
	Cucurbitacin D, I	Displayed cytotoxicity against Bel-7402 cells		< 1 μmol/L [IC50]	Meng et al[86]
	Echinocystic acid	Exhibited antiproliferative effect against HepG2 cells	↑apoptosis; ↓Bcl-2; ↑caspase-3, -9, -8; ↑PARP cleavage; ↓ΔΨm; ↓cyt. c; ↑p38; ↑JNK	15-100 μmol/L	Tong et al[87]
	Escin	Demonstrated inhibitory effects on cell viability of HepG2 cells	↑apoptosis; ⊥G1/S; ↑AIF; ↑cyt. c; ↑bax; ↓Bcl-2; ↓cyclin-E/cdk2; ↓pRb; ↓E2F	10-60 μg/mL	Zhou et al[88]
	Ganoderic acid	Demonstrated an inhibition in the growth of BEL 7402 cells	⊥G1/S	50-500 mg/mL	Yang[89]
	Ganoderiol F	Displayed antiproliferative effects in HepG2 , Huh7 and Hep3B cells	⊥G1; ↓DNA synthesis; ↓topo I and II; ↑p16; ↓p21; ↑pERK2	0.1-60 μmol/L	Chang et al[90]
	Ginsenoside-Rg1	Accelerated the growth of SK-Hep-1 cells	↑cyclin E; ↑cdk2	2.5-100 μmol/L	Lee et al[91]
	Ginsenoside-Rg5	Suppressed the growth of SK-Hep-1 cells	⊥G1/S; ↓cyclin E; ↓cdk2; ↑p21WAF1/CIP1; ↓cdc25A	0.1-25 μmol/L	Lee et al[92]
	Ginsenoside Rh2	Inhibited DNA synthesis in SK-Hep-1 cells	⊥G1/S; ↓cyclin E; ↑p27kip1; ↓cdc25A	0.25-100 μmol/L	Lee et al[93]
		Induced cell-death in SK-Hep-1 cells	↑apoptosis; ↑caspase-3; ↑PARP	2-12 mg/mL	Park et al[94]
	Ginsenoside Rk1	Inhibited the growth of HepG2 cells	↑apoptosis; ↑caspase-3, -8; ↓FADD; ↓telomerase activity	12.5-100 μmol/L	Kim et al[95]
		Exhibited antiproliferative effects on HepG2 cells	↑autophagy; ⊥G1	0-100 μmol/L	Ko et al[96]
	Ginsenoside Rs3	Displayed suppressive effects against the growth of SK-Hep-1 cells	↑apoptosis; ↓cyclin E, A; ↑p53; ↑p21WAF1/CIP1; ↓cdk2	0.1-25 μmol/L	Kim et al[97]
	Gypenosides	Exhibited cytotoxicity and decreased viability of Huh7, Hep3B and HA22T cells	↑apoptosis; ↑Bax; ↑Bak; ↑Bcl-XL; ↓Bcl-2; ↓Bad; ↑cyt. c; ↑caspase-3, -9, -8	0.1-400 mg/mL	Wang et al[98]
	IH-901	Conferred antiproliferative effects against HepG2 cells	↑apoptosis; ↑caspase-3, -8, -9; ↑PARP; ↑cyt. c	10-60 μmol/L	Oh et al[99]
		Inhibited the growth of SMMC7721 cells	↑apoptosis; ⊥G0/G1; ↑Bax; ↑p53; ↑cyt. c; ↓pro-caspase-3, -9	5-100 μmol/L	Ming et al[100]
	Kalopanaxsaponins A, I	Showed significant cytotoxicity against HepG2 and R-HepG2 cells	↑apoptosis	8.9-18.1 μmol/L	Tian et al[101]
	Keto- and acetyl-keto-boswellic acids	Exhibited antiproliferative effects in HepG2 cells	↑apoptosis; ⊥G1; ↑caspase-3, -8, -9	25-200 μmol/L	Liu et al[102]
	Lucidenic acid A,B,C, N	Displayed antiproliferative and anti-invasive effects against HepG2 cells	↓MMP-9; ↓ERK1/2; ↓NF-κB; ↓AP-1; ↓c-Jun; ↓c-Fos	10-100 μmol/L	Weng et al[103,104]
	Lupeol	Exhibited growth inhibitory effects against SMMC7721 cells	↑apoptosis; ↑caspase-3, -8; ↓DR3; ↑FADD	6.25-200 μmol/L	Zhang et al[105]
	25-Methoxyhispidol A	Showed antiproliferative effects against SK-Hep1 cells	↑apoptosis; ⊥G0/G1; ↓cyclin D1; ↓CDK4; ↓c-myc; ↓pRb; ↑p21	0.8-100 μmol/L	Hong et al[106]
	Oleanolic acid	Decreased the viability of HepG2, Hep3B, Huh7 and HA22T cells	↑apoptosis; ↓ΔΨm; ↑caspase-3, -8; ↓Na+-K+- ATPase; ↓ICAM-1; ↓VEGF	2-8 μmol/L	Yan et al[107]
		Reduced the viability of Huh7 cells	↑apoptosis; ↓ΔΨm; ↑Bax; ↓Bcl2; ↑cyt. c; ↑ caspase-3, -9; ↓NF-κB; ↓XIAP	20-100 μmol/L	Shyu et al[108]
	Ursolic acid	Inhibited the proliferation of HepG2 and R-HepG2 cells	↑apoptosis; ⊥G1/G0; ↓COX-2; ↑HSP105	3.125-100 μmol/L	Tian et al[109]
		Suppressed the proliferation of HepG2 cells	↑apoptosis; ↑p53; ↓Bcl-2; ↓survivin; ↑caspase-3; ↓PI3K/Akt	5-80 μmol/L	Tang et al[110]
		Decreased the viability of HepG2, Hep3B, Huh7 and HA22T cells	↑apoptosis; ↓ΔΨm; ↑caspase-3, -8; ↓Na+-K+- ATPase; ↓ICAM-1; ↓VEGF	2-8 μmol/L	Yan et al[107]
		Reduced the viability of Huh7 cells	↑apoptosis; ↓ΔΨm; ↑Bax; ↓Bcl2; ↑cyt. c; ↑ caspase-3, -9; ↓NF-κB; ↓XIAP	20-100 μmol/L	Shyu et al[108]
	Waltonitone	Conferred inhibitory effects on the growth of BEL-7402 cells	↑apoptosis; ↑caspase-3, -8, -9; ↑Bax; ↑cyt. c; ↑Fas; ↑FasL; ↑apaf-1	0.4-100 μmol/L	Zhang et al[111]
	Miscellaneous	Induced reduction in the viability of HepG2 and Hep3B cells		9.4-71.1 μmol/L [IC50]	Wang et al[112]
		Exhibited cytotoxicity against HepG2 cells	↑apoptosis; ↑p53; ⊥G1/S	0.5-80 μmol/L	Huang et al[113]
Tetraterpenes	Astaxanthin, β-Carotene	Suppressed the invasive characteristic of AH109A cells	Antioxidant mechanisms	2.5-20 μmol/L	Kozuki et al[114]
		Inhibited the migration of SK-Hep-1 cells		1-20 μmol/L	Huang et al[115]
		Delayed the proliferation and improved the differentiation of oval cells obtained from neoplastic liver	↑albumin; ↑fibrinogen; ↑hapatoglobin	5 μmol/L	Wójcik et al[116]
		Exerted genotoxic and cytotoxic effects in HepG2 cells	↑apoptosis; ↑necrosis; ↑TBARS	4-8 μmol/L	Yurtcu et al[117]
	Fucoxanthin	Inhibited the growth of HepG2 cells	⊥G0/G1; ↓cyclin D1, D3; ↓cdk4; ↓pRb	10-50 μmol/L	Das et al[118]
		Exhibited antiproliferative effect against SK-Hep-1 cells	↑apoptosis; ⊥G0-G1; ↑GJIC; ↑Cx43; ↑Cx32; ↓pJNK; ↓pERK; ↑[Ca]++	1-20 μmol/L	Liu et al[119]
	Lycopene	Suppressed the invasive property of AH109A cells		0.1-20 μmol/L	Kozuki et al[114]
		Induced an inhibitory effect on the growth of Hep3b cells	⊥G0/G1; DNA damage	0.1-50 μmol/L	Park et al[120]
		Displayed antimigration and anti-invasive activity in SK-Hep-1 cells	↑nm23-H1	1-20 μmol/L	Huang et al[115]
		Inhibited adhesion, invasion and migration of SK-Hep-1 cells	↓MMP-9, -2	0.1-50 μmol/L	Hwang et al[121]
		Inhibited SK-Hep-1 cell invasion	↓MMP-9; ↓NF-κB; ↑IκBα; ↓Sp1; ↓IGF-1R; ↓ROS	1-10 μmol/L	Huang et al[122]
Sesquiterpenes	α-Bisabolbol	Induced cytoxicity in HepG2 cells	↑apoptosis; ↑caspase-8, -9; ↑cyt. c; ↑Bax; ↑Bak; ↓Bcl-2; ↑p53; ↑NF-κB; ↑Fas	0.1-20 μmol/L	Chen et al[123]
	Dehydrocostuslactone	Inhibited the proliferation of HepG2 and PLC/PRF/5 cells	↑apoptosis; ↑Bax; ↑Bak; ↓Bcl-2; ↓Bcl-XL; ↑caspase-4, -9; ↑AIF; ↑Endo G; ↑ER stress; ↓CHOP/GADD153; ↑Bip; ↑MAPK; ↑pJNK; ↑ERK1/2; ↑p38	1-40 μmol/L	Hsu et al[124]
	Furanodiene	Inhibited cell growth of HepG2 cells	↑apoptosis; ⊥G2/M; altered ΔΨm; ↑cyt. c; ↑caspase-3; ↑pp38; ↓pERK1/2	0.1-1000 μmol/L	Xiao et al[125]
	HOBS1, HOBS2	Exhibited antiproliferative effects and induced redifferentiation in SMMC-7721 cells	⊥G1; ↓AFP; ↓γ-GT; ↓TAT	0.1-30 μg/mL	Miao et al[126]
	Zerumbone	Showed antiproliferative activity against HepG2 cells	↑apoptosis; ↓Bcl-2; ↑Bax	3.45 μg/mL [IC50]	Sakinah et al[127]

AFP: α-fetoprotein; AIF: Apoptosis-inducing factor; AP-1: Activator protein-1; apapf-1: Apoptotic protease activating factor 1; Cd: Cadmium; COX-2: Cyclooxygenase-2; Cx: Connexin; DR: Death receptor; cyt. c: Cytochrome c; GR: Glucocorticoid receptor; IC₅₀: Inhibitory concentration 50%; ER: Endoplasmic reticulum; ERα: Estrogen receptor α; ERK: Extracellular signal-regulated kinase; FADD: Fas-associated death domain; GLI1: Glioma-associated oncogene protein 1; GJIC: Gap junctional intercellular communication; γ-GT: γ glutamyl transferase; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; HSP, heat shock protein; ICAM-1: Intercellular adhesion molecule-1; IκB: Inhibitory κB; IKKα/β: IκB kinase α/β; IL-1β: Interleukin 1β; IL-6: Interlukin-6; IGF2: Insulin growth factor 2; IGF-1R: Insulin growth factor-1 receptor; JAK1: Janus-activated kinase 1; JNK: c-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; MD: Mitochondrial dehydrogenase; MMP: Matrix metalloproteinase; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor-κB; NO: Nitric oxide; PARP: Polypeptide poly(ADP-ribose) polymerase; PGE₂: Prostaglandin E₂; PhIP: 2-amino-1-methyl-6-phenylimidazol[4,5-b]pyridine; PI3K: Phosphatidylinositol 3-kinase; PKC: Protein kinase C; PMA: Phorbol 12-myristate; Pop: Population; PTCH1: Protein patched homolog 1; Rb: Retinoblastoma protein; ROS: Reactive oxygen species; Sp1: Stimulatory protein-1; SULT-1: Sulfotransferase-1; STAT3: Signal transducer and activator of transcription 3; TAT: Tyrosine-α-ketoglutarate transaminase; TPA: 12-O-tetradecanoylphorbol-13-acetate; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand; uPA: Urinary plasminogen activator; VEGF: Vascular endothelial growth factor; ΔΨm: Mitochondrial membrane potential; XIAP: X-linked inhibitor of apoptotic protein.

Table 2 In vivo effects of natural terpenoids on development and growth of liver cancer

Terpenoids	Compounds	Effects	Mechanisms	Dose/duration	Route	Ref.
Monoterpenoids	Auraptene	Suppressed DENA-induced TGF-α foci and carcinoma in male F344 rats	↑apoptosis; ↓cell proliferation	100-500 ppm; 7 wk	Diet	Sakata et al[128]
	Geraniol	Decreased GSTp foci and nodules during DENA-initiated and 2-AAF-promoted hepatocarcinogenesis in male Wistar rats	↓cell proliferation; ↑apoptosis	25 mg/100 g; 8 wk	po	Ong et al[129]
		Inhibited liver carcinogenesis with decrease in mean number of GSTp foci and nodule induced by DENA and promoted by PB in male Wistar rats	↑apoptosis; ↓RhoA activation	25 mg/100 g; 5 wk	po	Cardozo et al[130]
	d-Limonene	Decreased the number of GSTp foci in DENA-initiated and Glu-P-1-promoted hepatocarcinogenesis in male F344 rats		0.5%; 6 wk	Diet	Hirose et al[131]
		Exhibited chemopreventive effects against DENA/PB hepatocarcinogenesis in male AKR mice	↓c-jun; ↓c-myc	5%; 80 d	Diet	Giri et al[132]; Parija et al[133]
		Reduced the incidence, number and size of GSTp foci and neoplastic nodules induced by NNM in male Sprague-Dawley rats	↑apoptosis; ↓cell proliferation	1%, 2%; 7 wk	Diet	Kaji et al[134]
		Suppressed hepatic preneoplasia and tumor growth induced by DENA in male WR rats	↑GJIC	3 mL/kg per day; 5 times/wk; 5.5 mo	po	Bodake et al[135]
	Perillyl alcohol	Inhibited liver tumor growth induced by DENA in male F344 rats	↑ apoptosis; ↑TGFβ; ↑M6P/IGFII R; ↑TGFβ type I, II, III R	1% w/w for 1 wk and 2% w/w for 18 wk	Diet	Mills et al[136]
Diterpenoids	Andrographolide	Suppressed the formation of BHC- induced nodules in Swiss male albino mice	↑GSH; ↑GR; ↑GPX; ↑SOD; ↑CAT; ↓GGT; ↓GST	5-10 mg/kg per day; 1-8 mo	po	Trivedi et al[137]
		Reversed histomorphological and ultrastructural changes during BHC-induced hepato-carcinogenesis male Swiss mice	↑G-6-Pase; ↑ATPase; ↑SDH; ↓SGPT; ↓SGOT; ↓ALP; ↓OCT; ↓ACP	5,7 and 10 mg/kg; 1-8 mo	Diet	Trivedi et al[138]
	Epoxy clerodane diterpene	Reduced incidence, multiplicity and size of nodules induced by DENA in male Wistar rats	↓SGOT; ↓SGPT; ↓LDH; ↑SOD; ↑CAT; ↓GST; ↓GGT; ↑GSH; ↑GPX	10 mg/kg per day; 8 wk	po	Dhanasekaran et al[139]
	Excisanin A	Suppressed tumor growth in BALB/c nude mice implanted with Hep3B cells	↓apoptosis; ↓pAKT	10-20 mg/kg; 12 d	ip	Deng et al[70]
	Geranylgeraniol	Reduced the incidence, number and size of visible nodules and GSTp foci in DENA/2-AAF hepatocarcinogenesis in male Wistar rats	↓cell proliferation; ↓DNA strand break; ↓plasma cholesterol; ↓NF-κB p65	8-16 mg/kg per day; 7 wk	po	de Moura Espíndola et al[140]
Triterpenoids	Bacoside A	Delayed the development and growth of neoplastic nodules induced by DENA in male Wistar albino rats	↓lipid peroxidation; ↑Vit A; ↑Vit E; ↑GSH; ↓ROS; ↓AFP; ↓CEA; ↓5’-nucleotidase; ↓ALT; ↓AST; ↓LDH; ↓ALP; ↓GGT; ↑SOD; ↑CAT; ↑GPX; ↑GR; ↓MMP-2; ↓MMP-9	15 mg/kg; 16 wk	po	Janani et al[141,142]
	Cucurbitacin B	Decreased HepG2 tumor volume and inhibited tumor growth in mice xenograft model		26-110 µg/kg per day; 12 d	po	Zhang et al[83]
		Inhibited tumor growth in BEL-7402 xenografted mice model		0.1-3 mg/kg; twice per day for 26 d	po	Chan et al[84]
	Escin	Demonstrated inhibitory effects on tumor growth in H22 tumor- bearing female Kunming mice		1.4-2.8 mg/kg; 7 d	ip	Zhou et al[88]
	Ginseng extract	Inhibited AFB1-initiated and FB-promoted hepatocarcinogenesis in female SD rats	↓ALT; ↓AST; ↑albumin; ↓TG; ↓cholesterol; ↓LDL; ↑HDL; ↓AFP, ↓CEA, ↓MDA, ↑TAC; ↓fibrosis	150 mg/kg; 1-12 wk	po	Abdel-Wahhab et al[145]
	Glycyrrhizin	Decreased the incidence of nodules and HCC induced by DENA in BALB/c mice	↑albumin; ↑AST	2 mg/animal; 3 d/wk for 12-32 wk	im	Shiota et al[146]
		Reduced the size, volume and number of preneoplastic liver lesions initiated by DENA and promoted with 2-AAF in male SD rats		0.1% 25 mg/kg; 1 wk	po	Wan et al[147]
	EC-2, EC-4	Failed to show modifying effects against DENA-induced hepato-carcinogenesis in male F-344 rats		1 mg/kg; 5 times a week for 2-8 wk	po	Karim et al[148]
	Squalene	Failed to exhibit chemoprevention against DENA-initiated and 2-AAF- promoted hepatocarcinogenesis in male Wistar rats	↑ plasma cholesterol	1-1.5 g/kg; 8 wk	po	Scolastici et al[149]
	Ursolic acid	Inhibited the growth of H22 hepatoma implanted in male CD-1 mice		15-30 mg/kg; 10 d	ip	Tian et al[109]
		Suppressed DENA-initiated and PB- promoted hepatocarcinogenesis in male Wistar rats	↓MDA; ↓PC; ↓membrane damage; ↑Na+K+ ATPase; ↑Mg2+ ATPase; ↑Ca2+ ATPase	20 mg/kg per day; 6 wk	po	Gayathri et al[150]
	Waltonitone	Delayed the growth of tumors in athymic nude BALB/c nu/nu mice implanted with BEL-7402 cells	↑cleaved caspase-3, -9; ↓pro-caspase-9	20-50 mg/kg; Once in 2 d for 15 d	iv	Zhang et al[111]
Tetraterpenoids	α-Carotene	Decreased the number of hepatomas during spontaneous hepatocarcinogenesis in male C3H/He mice		0.005%-0.05%; 40 wk	dw	Murakoshi et al[151]
		Reduced the number of liver tumors in multi-organ carcinogenesis in male and female B6C3F1 mice		0.4 mg/mouse; three times a week for 24 wk	po	Tsuda et al[152]
	β-Carotene	Failed to have an effect on the number and size of preneoplastic liver foci induced by DENA/2-AAF/PB in male Wistar rats		300 mg/kg diet or 10 mg/kg bw (3 times/wk); 3 wk	Diet; ip	Astorg et al[153]
		Failed to exhibit any effect on 2-NP- or DENA-initiated hepato- carcinogenesis in male Wistar rats		300 mg/kg diet; 3 wk	Diet	Astorg et al[154]
		Did not modify DENA-initiated and PCB-promoted hepatocarcinogene-sis in female Sprague-Dawley rats		0.5%; 12 wk	Diet	Tharappel et al[155]
		Inhibited the development of preneoplastic foci and nodules initiated with DENA and promoted by 2-AAF in male Wistar rats		70 mg/kg; alternate d for 2-8 wk	po	Moreno et al[156]
		Reduced the generation of nodules and GGT foci induced by DENA/2-AAF in male Wistar rats		70 mg/kg; 8 wk	po	Moreno et al[157]
		Decreased the incidence and total number of GGT foci and nodules in DENA-initiated and 2-AAF-promoted hepatocarcinogenesis in male Wistar rats	Remodeling of lesions	70 mg/kg; 5 wk	po	Rizzi et al[158]
		Attenuated the development of GSTp foci in the resistant hepatocyte model in male Wistar rats	↓oval cell reaction	70 mg/kg; alternate d for 8 wk	po	Dagli et al[160]
		Suppressed progression of hepatocarcinogenesis induced by DENA in male Wistar rats	↓cell proliferation	70 mg/kg; 8 wk	po	Moreno et al[161]
		Exerted chemoprevention of initiation phage of DENA-induced hepatocarcinogenesis in male Wistar rats	↓cell proliferation; ↓DNA damage; remodeling of lesions	70 mg/kg; 8 wk	po	Ambrogi et al[162]
		Conferred a weak chemopreventive effect against DMH-initiated hepatocarcinogenesis in male Wistar rats		70 mg/kg; 9 wk	po	Sampaio et al[163]
		Decreased the incidence, number and size of nodules induced by 2-AAF in male Sprague-Dawley rats	↑cyt. b5; ↑CYP; ↑NADPH cyt. c reductase; ↑AHH; ↓UDPGT; ↓GST	100 mg/kg diet; 4-20 wk	Diet	Sarkar et al[164]
		Suppressed 3’-Met-DAB-induced nodulogenesis in male Sprague-Dawley rats	↓GSH; ↓GGT; ↓GST; ↓GPX; ↓GR; ↑Vit A	120 mg/kg diet; 4-20 wk	Diet	Sarkar et al[165]
		Decreased DENA-initiated and PB-promoted nodule incidence and area in male Sprague-Dawley rats	↓RBC protein damage; ↓lipid peroxidation; ↑G-6-Pase; ↓SOD; ↓CAT	120 mg/kg diet; 4-20 wk	Diet	Sarkar et al[166]
		Suppressed DENA-induced hepatic chromosomal aberrations in male Sprague-Dawley rats	↓frequency of chromosomal aberrations; ↓DNA chain breaks	120 mg/kg per day; 15-45 d	Diet	Sarkar et al[167]
		Reduced the incidence, total number, multiplicity and size of nodules in DENA/PB hepato-carcinogenesis in male Sprague-Dawley rats	↓GSH; ↓GGT; ↓GPX; ↑CYP; ↑GST	500 mg/kg; 4-20 wk	po	Bishayee et al[168]
		Decreased the number and size of GSTp foci in IQ-initiated and PB- promoted hepatocarcinogenesis in male Fischer rats		0.02%; 8 d	Diet	Tsuda et al[169]
		Inhibited the development of GSTp foci and HCC induced by EE in female Wistar rats		250 mg/kg diet; 1-12 mo	Diet	Ogawa et al[170]
		Reduced the development of GSTp foci in Glu-P-1-induced hepato-carcinogenesis in male F344 rats		0.1%; 6 wk	Diet	Hirose et al[131]
		Inhibited carcinogen-DNA adduct formation induced by IQ in male F344 rats	↓CYP1A1; ↓CYP1A2	0.02%; 8 d	Diet	Uehara et al[171]
		Reduced the number of liver tumors in multi-organ carcinogenesis in male B6C3F1 mice		0.4 mg/mouse; three times a week for 24 wk	po	Tsuda et al[152]
		Reduced AFB1-induced hepato-carcinogenesis in male Wistar rats		300 ppm; 3 wk	Diet	Gradelet et al[172]
		Decreased the number and volume of GSTp foci initiated by AFB1 in male Wistar rats		300 mg/kg diet; wk	Diet	Gradelet et al[173]
		Inhibited liver tumor formation induced by DMBA in both male and female toads		0.05 mg/toad; twice a week for 12 wk	sc	Sadek et al[174]
		Suppressed the formation of GSTp foci and nodules initiated with DENA and promoted by PB in male Sprague-Dawley rats	↓GSH; ↓GST; ↑O2 consumption	120 mg/kg; 16 wk	Diet	Chattopadhyay et al[175]
		Reversed histomorphological changes during DENA-induced hepatocarcinogenesis in male Sprague-Dawley rats	↓DNA SSB; ↓K; ↑Ca; ↓Mn; ↓Fe; ↑Cu; ↑Zn; ↓Se	120 mg/kg; 16 wk	Diet	Chattopadhyay et al[176]
	Carotenoids (astaxanthin, β-apo-8’-carotenal, canthaxanthin)	Did not modify DENA/2-AAF/PB hepatocarcinogenesis in male Wistar rats		300 mg/kg diet; 3 wk	Diet	Astorg et al[153]
		Failed to exhibit any effect on 2-NP- or DENA-initiated liver carcinogenesis in male Wistar rats		300 mg/kg diet; 3 wk	Diet	Astorg et al[154]
		Attenuated the number and size of GSTp foci induced by AFB1/2-AAF in male Wistar rats	↓DNA single strand breaks	300 ppm; 3 wk	Diet	Gradelet et al[172]
		Reduced initiation of liver carcinogenesis by AFB1 in male Wistar rats	↓AFB1-DNA binding; ↓DNA single strand breaks; ↑AFB1 metabolism	300 mg/kg diet; 3 wk	Diet	Gradelet et al[173]
	β-Ionone	Reduced the incidence, number and size of GSTp foci and nodules in the initial phase of DENA/2-AAF hepatocarcinogenesis in male Wistar rats	↓cell proliferation; ↓plasma cholesterol; ↓DNA damage	80 160 mg/kg; 7 wk	po	de Moura Espíndola et al[140]
		Inhibited GSTp foci and nodules during promotional phase of DENA/2-AAF hepatocarcino-genesis in male Wistar rats	↓cell proliferation; ↓HMGCoA reductase	160 mg/kg; 5 wk	po	Cardozo et al[130]
	Lutein	Reduced the number and size of GSTp foci initiated by DENA and promoted with 2-AAF in male Wistar rats	↓DNA strand breaks	70 mg/kg per day; 8 wk	po	Toledo et al[181]
		Reduced the size of nodules during the promotional phase of DENA/2-AAF hepatocarcinogenesis in male Wistar rats	↓DNA damage	70 mg/kg; 2-6 wk	po	Moreno et al[182]
	Lycopene	Failed to modify AFB1-induced hepatocarcinogenesis in male Wistar rats		300 ppm; 3 wk	Diet	Gradelet et al[172]
		Exhibited no effect on the initiation of hepatocarcinogenesis induced by AFB1 in male Wistar rats		300 mg/kg diet; 3 wk	Diet	Gradelet et al[173]
		Failed to influence the risk of developing spontaneous HCC in male Long-Evans Cinnamon rats		0.005% w/w; 70 wk	Diet	Watanabe et al[183]
		Decreased the volume of GGT and GSTp foci in DENA-initiated and 2-AAF-promoted liver carcinogenesis in male Wistar rats	↓CYP2E1	300 mg/kg diet; 3 wk	Diet	Astorg et al[154]
		Attenuated the number and size of GSTp foci initiated by DENA and promoted with 2-AAF in male Wistar rats	↓DNA strand breaks	70 mg/kg per day; 8 wk	po	Toledo et al[181]
		Decreased the number of GSTp foci in DENA-initiated and PCB-promoted hepatocarcinogenesis in female Sprague-Dawley rats		1%; 12 wk	Diet	Tharappel et al[155]
		Inhibited DENA-initiated and NASH-promoted GSTp foci development in male Sprague-Dawley rats	↓PCNA; ↓cyclinD1; ↓lipid peroxidation; ↑Nrf2; ↑HO-1; ↓pERK; ↓NF-κB p65	15 mg/kg per day; 6 wk	Diet	Wang et al[184]
	Tomato extract	Reduced the number of GSTp foci initiated by DENA and promoted by NASH in male Sprague-Dawley rats	↓PCNA; ↓cyclinD1; ↓TNF-α; ↓IL-1β; ↓IL-12; ↓lipid peroxidation; ↓CYP2E1; ↓pERK; ↓NF-κB	250 mg/kg per day; 6 wk	Diet	Wang et al[184]
Sesquiterpenoids	Dehydrocostus-lactone	Inhibited tumor growth in nude mouse implanted with PLC/PRF/5 cells	↑apoptosis; ↑pPERK; ↑IRE-1	10 mg/kg per day; 45	ip	Hsu et al[124]
	Farnesol	Suppressed the development of GSTp foci and nodules initiated with DENA and promoted by 2-AAF in male Wistar rats	↓cell proliferation; ↓DNA damage; ↓plasma cholesterol; ↓HMG-CoA reductase	250 mg/kg; 8 wk	po	Ong et al[129]
	Zerumbone	Reduced DENA/2-AAF- induced hepatocarcinogenesis in Sprague- Dawley rats	↓ALP; ↓ALT; ↓AST; ↓AFP; ↓lipid peroxidation; ↓GSH; ↓PCNA; ↑Bax; ↓Bcl-2	15, 30 or 60 mg/kg; twice a week for 11 wk	ip	Taha et al[186]

2-AAF: 2-acetylaminofluorene; AFB-1: Aflatoxin B1; AFP: α-fetoprotein; AHH: Aryl hydrocarbon hydroxylase; AHF: Altered hepatic foci; ALA-S: δ-aminolevulinate synthetase; ALP: Alkaline phosphatase; ALT: Alanine transaminase; AST: Aspartate transaminase; BHC: Benzene hexachloride; CA: Chromosomal aberrations; CAT: Catalase; CEA: Carcinoembryonic antigen; CYP: Cytochrome P-450; CYP2E1: Cytochrome P-450 2E1; DAB: 1,4,-dimethylaminoazobenzene; DENA: Diethylnitrosamine; DMH: 1,2-dimethylhydrazine; dw: Drinking water; EAF: Enzyme altered foci; EC-2: 3,4-Seco-8βH-ferna-4-(23),9(11)-dien-3-oic acid; EC-4: 3,4-Seco-oleana-4-(23),18-dien-3-oic acid; EE: Ethynlyestradiol; ERK: Extracellular signal-regulated kinase; FB: Fumonisin; GGT: γ-glutamyl transpeptidase; GJIC: Gap-junctional intercellular communication; Glu-P-1: 2-amino-6-methyldipyrido[1,2-α:3’,2’-d] imidazole; G-6-Pase: Glucose-6-phosphatase; GPX: Glutathione peroxidase; GR: Glutathione reductase; GSTp: Glutathione S-transferase, placental form; GSH: Reduced glutathione; HCC: Hepatocellular carcinoma; HDL: High-density lipoprotein; HO-1: Heme oxygenase-1; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; HTHQ: 1-O-hexyl-2,3,5-trimethylhydroquinone; IL: Interleukin; ip: Intraperitoneal; po: Per os; im: Injectio intramuscularis; sc: Subcutaneous route; IQ: 2-amino-3-methylimidazo[4,5-f]quinoline; JNK: c-Jun N-terminal kinase; LDH: Lactate dehydrogenase; LDL: Low-density lipoprotein; MAPK: Mitogen-activated protein kinase; MDA: Malondialdehyde; M6P/IGFII-R: Mannose 6-phosphate/insulin-like growth factor II receptor; 3’-Met-DAB: 3’-methyl-4-dimethlyaminoazobenzene; MMP: Matrix metalloproteinase; MPE: Mango pulp extract; NASH: Nonalcoholic steatohepatitis; NF-κB: Nuclear factor κB; NMDA: N-nitrosodimethylamine; NNM: Nitrosomorpholine; NMU: N-nitrosomethyl urea; 2-NP: 2-nitropropane; Nrf2: NF-E2-related factor 2; OCT: Ornithine carbamoyltransferase; PB: Phenobarbital; PC: Protein carbonyl; PCB: 3,3′,4,4′-tetrachlorobiphenyl; PCNA: Proliferating cell nuclear antigen; RBC: Red blood cell; ROS: Reactive oxygen species; sc: Subcutaneous; SD: Sprague-Dawley; SDH: Succinate dehydrogenase; SGPT: Serum glutamic pyruvic transaminase; SGOT: Serum glutamyl oxalate transaminase; SOD: Superoxide dismutase; SSB: Single stranded breaks; SULT-1: Sulfotransferase-1; TAC: Total antioxidant capacity; TAT: Tyrosine ketoglutarate; TG: Triglyceride; TGF: Transforming growth factor; TNF: Tumor necrosis factor; Vit: Vitamin; YY1: Ying Yang 1 protein.