Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma

Table 7

Silibinin in HCC with possible mechanisms discussed in this paper.

Subfamily	Flavonoids	Typical origin	In vitro/in vivo; Cell lines/modes; Effective dose	Effects and related mechanisms	Author (year); References
Flavonolignans	Silibinin	Extract of the milk thistle seeds; Milk thistle plant   (Silybum marianum)	In vitro; SNU761 cell line, Huh-BAT cell line; 100 M	↓ EGFR-dependent Akt signaling; ↑ growth-inhibiting effects of both gefitinib and sorafenib	Gu et al. (2015) [30]
			In vitro/in vivo; HepG2 cells/male athymic nude mice; 5, 10, or 20 M (↓ tumor cell adhesion, migration); 50, 100, and 200 M/200, 400 mg/kg/day (5 days/week)	↓ tumor cell adhesion, migration, ↓ GSH, ↓ T-AOC ↑ apoptotic index, ↑ caspase-3, and ↑ ROS; ↓ notch signaling via ↓ Notch1 intracellular domain (NICD), ↓ RBP-Jκ, and ↓ Hes1 proteins,; ↑ Bax, ↓ Bcl2, ↓ survivin, and ↓ cyclin D1	Zhang et al. (2013) [29]
			In vivo; HuH7 xenografts; 80 and 160 mg/kg/day	↓ Ki-67 and ↓ α-FP production, ↓ NF-B content, ↓ polo-like kinase 1, ↓ Rb phosphorylation, and ↓ E2F1/DP1 complex; ↑ p27/CDK4 complex and CPK 1 expression; mediated by ↓ G1-S transition of the cell cycle; ↓ survivin phosphorylation; ↓ cell proliferation; ↓ p-ERK, ↑ PTEN/PI(3)K/Akt, and ↑ ERK pathways; ↑ AC-H3 and AC-H4 expression and ↑ SOD-1	Cui et al. (2009) [111]
			In vitro; Hep3B; 500 M	↓ cell proliferation; ↓ HIF-1α and; ↓ mTOR/p70S6K/4E-BP1 signalling pathway	García-Maceira et al. (2009) [112]
			In vitro; HepG-2; 25, 50 and 75 M	↓ cell proliferation, ↓ MMP 2 enzymatic activity, ↓ NO; ↓ ERK 1/2, ↑ RKIP, Spred-1, and Spred-2; ↓ cell growth and proliferation via ↓ Hec1, and MMP-2	Momeny et al. (2008) [43]
			In vitro; HuH7 cells; 240 mol/L	↑ p21/CDK4 and p27/CDK4 complexes,; ↓ Rb-phosphorylation ↓ E2F1/DP1 complex; ↓ survivin ↑ caspase-3 and ↑ caspase-9; antiangiogenic effects via ↓ MMP2 and ↓ CD34; ↑ PTEN and ↓ p-Akt production; ↑ AC-H3 and AC-H4	Lah et al. (2007) [113]
			In vitro; HepG2 and Hep3B cells; 100–300 mol/L	↑ G1 arrest in HepG2 and ↑ G1 and G2-M arrests in Hep3B cells; ↑ Kip1/p27, ↓ cyclin D1, ↓ cyclin D3, ↓ cyclin E, ↓ CDK-2, and ↓ CDK4; ↓ G2-M regulators, ↓ CDK2, ↓ CDK4, and ↓ CDC2 kinase activity	Varghese et al. (2005) [114]

For abbreviations see footer of Table 1.