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.