Current therapeutic modalities and chemopreventive role of natural products in liver cancer: Progress and promise

Table 1 Effect of natural products on liver cancer

Natural products	Extract/phytochemicals	Experiment model (in vitro/in vivo/clinical trials	Tested concentration	Medicinal effects	Ref.
Broccoli	Sulforaphane	In vitro (murine hepatoma Hepa 1c1c7 and human HepG2 cells)	1-20 μmol/L	Sulforaphane showed positive effect on Phase II detoxification enzyme. Sulphoraphane treatment resulted in increased expression of CYP1A1 and quinone reductase	[116]
Grape	Procynidins rich grape crude extract	In vitro (HepG2 human liver cancer cells)	0-120 μg/mL	Grape extract in concentrations greater than 20 μg/mL (20.4 μmol/L) was cytotoxic to HepG2 human liver cancer cells, with maximal toxicity of 67.2% and ED50 of 49.6 μg/mL (50.5 μmol/L)	[117]
	Flavan-3-ol rich extract	In vitro HepG2 and breast cancers (MCF-7) cells	0-60 μg/mL	Grape extract showed dose dependent cytotoxicity via Induction of apoptosis, DNA damage and suppression of oncoprotein Her-2 expression. Treatment also resulted in increased NO production in cancer cell	[118]
Mung bean sprouts	Extract	In vitro [Human cervical (HeLa) and hepatocarcinoma cells (HepG2)]	9.37 to 300 mg/mL	Mung bean sprouts was found to be a potent anticancer agent. The cytotoxic effect of Mung bean sprouts extract on HeLa, expressed as IC50, was 13.3 mg/ml 163.97 mg/ml while on HepG2 cells was 14.04 mg/ml. It also increases apoptosis, anti-tumor cytokines (TNF-and IFN-β), IFN-γproduction and subsequently up regulated the cell-mediated immunity	[119]
Cinnamon	Isoobtusilac-tone A	In vitro (Hep G2 cells)	100 μmol/L	Induces apoptosis in cancer cell	[120]
Ginger	6-shogaol, 6-gingerol	In vitro (Human hepatoma HepG2 and Hep3B cells)	10 μmol/L and 50 μmol/L	The migratory and invasive activity of HepG2 and Hep3B cells were decreased in doses dependent manner post 6-shogaol, 6-gingerol treatment. It suppresses the metastatic activity via down regulation of matrix metalloproteinase (MMP)-9 and urokinase type plasminogen and upregulation of tissue inhibitor metalloproteinase protein	[108,121]
Asparagus	asparanin A	In vitro (HepG2 cells)	0-30 μmol/L	Treatment with asparanin A resulted in cell cycle arrest at G2/M phase and apoptosis in HepG2 cells. Following treatment of HepG2 cells with asparanin A, cell cycle-related proteins including cyclin A, Cdk1 and Cdk4 were down-regulated, while p21WAF1/Cip1 and p-Cdk1 (Thr14/Tyr15) were up-regulated	[122]
Tomato	Tomatine	In vitro (HepG2 cells)	10, 50 and 100 μg/mL	Induces antigen-specific cellular immunity and direct destruction of cancer cell membranes	[123]
	Lycopene	In vivo (N-nitrosodiethylamine induced hepatocarcinogenesis in female Balb/c mice)	5 mg/kg bw	Lycopene treatment causes modulation of apoptosis related genes (enhanced expression of caspase 3 and 9 and p53 and decreased expression of Bcl-2). Lycopene exhibits pro-oxidant activity in tumor that supports observed enhanced apoptosis. This increased apoptosis is a chemopreventive action of lycopene in liver cancer	[124]
Plum	Extract	Benzopyrene-induced hepatocarcinogenesis in rats	2.5 or 5 g/kg bw	Plum extracts may counteract toxic effects of carcinogens and benzopyrene, and therefore have chemopreventive efficacy	[125]
Pomegranate	Emulsion	Diethylnitrosamine (DENA)-induced hepatocarcinogenesis inrat	1 or 10 g/kg bw	Treatment for 18 wk in rats resulted in reduced incidence, number, multiplicity, size and volume of hepatic nodules, precursors of HCC. It showed chemoprevention through potent antioxidant activity as the expression of Nrf-2 is increased in pomegranate treated rats	[126]
Citrus fruit	Auraptine	Diethylnitrosamine (DEN)-induced hepatocarcinogenesis in rat	5 or 10 g/kg bw	It suppresses tumor progression in DEN- challenged rats by negative selection for cancer cells with β-catenin mutation	[127]
Pepper	Glycoprotein	In vivo (DEN induced hepatocarcinogenesis in mice)	20 mg/kg bw	Pepper glycoprotein of 24 kDa treatment in rats causes increased activity of natural killer cell and ultimately prevention of DENA induced liver carcinogenesis via immunomodulation and promotion of apoptosis	[128]