Table 2.

Preclinical studies showing apoptotic effects of quercetin on liver cancer.

Type of Cancer	Cells	Effects	Mechanistic Insight	Concentration	References
Hepatocellular	HepG2	Induces Apoptosis, Cell Cycle arrest	↓ Proliferation of cancer cells, ↑ cell cycle arrest at S and G1 phase, ↑ necrotic and apoptotic cells,	Quercetin 20 to 220 µM or sorafenib 5 to 40 µM)	[78]
Hepatocellular	HepG2	Induces Apoptosis	↓ Cell proliferation, ↓ Bcl-2, ↓ mitochondrial mass, ↓ mitochondrial membrane potential, ↑ mitochondrial superoxide anion, ↑Caspases 3/7/9, ↓↑ BAX,	Quercetin and Permethylated Anigopreissin A (PAA) (inhibitors of hGDH1)-1,2,4,8,12 and 16 μM	[94]
Hepatoblastoma	HepG2, HuH-6 and HepT1	Induces Apoptosis,	↑ SIRT6, upregulation of SIRT6, suppressed cell proliferation and invasion, promoted cell apoptosis, ↓ frizzled 4 (FZD4) transcription, ↓ FZD4 and H3K9ac, ↓ Wnt5a, β-catenin, cyclin D1 and c-Myc	0, 60 and 120 mM	[95]
Hepatocellular	HepG2, Huh-7 (Gemcitabine resistant)	Induces Apoptosis, Cell Cycle arrest	↓ Proliferation of gemcitabine resistant cancer cells, ↑ apoptosis frequency, ↑ gemcitabine efficacy, ↑ accumulation of HepG2 cells in S phase, ↓ G1 and G2/M phase populations, ↑ p53, ↓ cyclin D1	Quercetin 0, 10, 25, 50, 100, or 200 μM or 0, 10, 25, 50, 100, and 200 nM Gemcitabine	[95,96]
Liver	KIM-1, KYN-1, KYN-2, KYN-3, HAK-1A, HAK-1B, HAK-2, HAK-3, HAK-4, HAK-5, and HAK-6	Induces Apoptosis, Cell Cycle arrest	↓ Cell proliferation, ↓ viable cell count, ↑ apoptosis frequency, G0/G1, G2/M and S phase cell cycle arrest	0–100 μM	[77]
Hepatocellular	HepG2 and Huh7	Induces Apoptosis	↓ cell viability and colony growth, ↑ apoptotic pathway, ↑ caspases ↑ Bax	100–500 μM	[97]
Hepatocellular	HepG2	Induces Apoptosis,	↑ cell viability, ↑ caspase-3 and 8, ↑ loss in cell connections, ↑ cell shrinkage, ↑ cell surface detachment, ↑ cytoplasmic density, ↑ dead cells, ↑ Bax, Bid, Bad, and p53, ↓ Bcl-2 and Bcl-XL, ↑ GRP78 and CHOP	Combination of naringenin, quercetin, and naringin and balsamin IC50 values for Nar, Nir and Qu are 150 mM, 20 mM and 37 mM, respectively, and 25 µg/mL of balsamin	[98]
Hepatocellular	SMMC7721 and HepG2	Induces Apoptosis, Cell Cycle arrest	↓ Growth of HCC cells, ↑ autophagosomes and autolysosomes, ↑ LC3A/B-II and beclin1, ↓ p62, ↓ phosphorylated AKT, mTOR, p70S6K and 4EBP1, ↑ phosphorylated JNK, ERK1/2 and p38MAPK	IC50’s at 21.0 and 34.0 μM	[48]
Hepatocellular	LM3	Induces Apoptosis, Cell Cycle arrest	↓ Cancer cell viability, ↑ apoptosis frequency, ↑ cleaved DNA, ↑ cells were arrested in the S and G2/M phases, ↓ G0/G1 phase cells, ↓ vimentin and MMP9, ↓ invasion and migration, ↑ LC3, ↓ p-STAT3	0, 20, 40, 60, 80, 100,120, 140, 160, and 200 µmol/L	[32]
Hepatocellular	HepG2	Induces Apoptosis, Cell Cycle arrest	↓ Proliferation of cancer cells, ↓ intracellular ROS level, ↓cyclin E and SOD1	--	[99]
Hepatocellular	HepG2	Induces Apoptosis	↓ Cell viability, ↑ cell apoptosis, ↓ chymotrypsin-like activity of proteasome, ↑ cleaved caspase-3, ↓ Bcl-2, ↑ p38 MAPK and JNK phosphorylation, ↓ ERK1/2 phosphorylation	0, 25, 50, and 100 µM	[62]
Liver	MHCC97H, Hep3B, HCCLM3 and Bel7402	Induces Apoptosis,	↓ Cancer cell proliferation, cell migration and colony formation, ↑ caspases, ↑ cytochrome c, ↓ NF-κB ↓ Akt and ERK1/2, P-27 was expressed highly, ↓ c-Myc, ↓ cyclin-D1, ↓ CDK1, ↓ MMP7, ↓ β-catenin,	Gold-quercetin -poly(DL-lactideco-glycolide) nanoparticles-0,10,20,30,40,50 and 50 µg/mL	[49]
Hepatocellular	SMMC-7721, HepG2 and HuH-7	Induces Apoptosis	↑ ZD55-TRAIL ↑ caspases and cleaved PARP, ↓ ZD55-TRAIL mediated NF-κB activation, ↑ pro-apoptotic action of ZD55-TRAI, ↓ Bcl-2, ↑ Bax	ZD55-TRAIL adenovirus-1,2,5,10 MOI + Quercetin 5, 10, 25, 50 μM	[79]
Hepatocellular	HepG2 and SMCC-7721	Induces Apoptosis, Cell Cycle arrest	↓ Cell proliferation, ↑ apoptosis, ↑ Bad and Bax, ↓ Bcl-2 and Survivin, ↑ 5-fluorouracil (5-FU) therapeutic efficacy, ↓ cells in S phases, ↑ cells in the G0/G1 phase	0.05, 0.1, and 0.15 mmol/L	[28]
Hepatocellular	HepG2	Apoptosis	↓ Cell growth, ↑ apoptosis, ↑ nuclear condensation and fragmentation, ↓ Sp1 and Sp1 regulatory protein, ↑ p27, p21, ↑ Bax, ↑ caspases and cleaved PARP	10–100 µM	[100]
Liver	HepG2 and Hep3B	Induces Apoptosis, Cell Cycle arrest	↑ Apoptosis, ↑ caspase-3, -8 and -9, ↓ phosphorylation of ERK and p38MAPK, ↑ phosphorylation JNK, ↓ PKC, entering the S and the G2/M phases gradually decreased, while most cells were blocked in the G1 phase	0, 100, 200, 400 and 800 µM	[101]
Hepatocellular	HepG2	Induces Apoptosis	↓ Cell proliferation, blockade of the cell cycle in the S-phase, ↓ DNA topoisomerase II, ↑ DNA fragmentation, ↑ caspase-3, ↑ apoptosis frequency	1, 10, 50, 100, 150 and 200 μM	[102]
Hepatoma	HepG2	Induces Apoptosis	↓Cell viability, ↑ ROS generation, ↑ caspase-3 and -9, ↑↓ caspase-8, ↓ Bcl-xL:Bcl-xS ratio, ↑ translocation of Bax to the mitochondrial membrane, ↓ Akt and ERK	0–100 μM	[30]
Hepatoma	H22, LL/2	Induces Apoptosis	↓ cell proliferation, ↑ apoptotic cell (sub-G1 cells)	0,5,10 and 15 μg	[103]