Roles of conventional and complementary therapies in recurrent hepatocellular carcinoma

Table 1 Compounds for reducing multicentric tumor occurrence by inducing autophagy, apoptosis and cell cycle arrest in hepatocellular carcinoma

Compound or Chinese herbal medicine	Cell line	Molecular mechanism	Effect	Ref.
Piperidine alkaloids	HepG2, Hep3B	Modulate Mst1-JNK pathway, ERK pathway, PINK1/Parkin axis and PTEN/AKT pathway	↑Autophagy, apoptosis, mitochondrial fission. ↓Proliferation	Liu et al[5]
Isoquinoline alkaloids	SMMC-7721, HCCLM9, Huh7, HepG2	Modulate AKT pathway, AKT/FoxO3a/Skp2 axis, PI3K/AKT-mTOR pathway, Wnt/β-catenin-mediated pathway and anthranilic acid metabolic pathway	↑Autophagy, apoptosis, cell cycle arrest. ↓Proliferation	Liu et al[5]
Indole alkaloids	HepG2, SMMC-7721, Hepa1-6, BEL-7404, Hep3B, Huh7	Modulate NOD1 pathway, AKT pathway and WWOX-dependent pathway	↑Apoptosis, cell cycle arrest. ↓Proliferation	Liu et al[5]
Terpenoids alkaloids	HLE, L-02, BEL-7402, HepG2	Modulate AKT, p53, caspase-3, MAPK, AFP, Ras	↑Apoptosis, cell cycle arrest. ↓Proliferation	Liu et al[5]
Steroidal alkaloids	HepG2, SMMC-7721, Hep3B	↑Gene expression of human TNFR I	↑Necroptosis, apoptosis, cell cycle arrest. ↓Proliferation	Liu et al[5]
Quinoline alkaloids	HepG2, L-02, QGY-7703	Modulate MMP-9, PCNE, ANT3 and VEGF	↑Necroptosis, apoptosis	Liu et al[5]
Solamargine	HepG2, Huh7	Modulate miR-192-5p/CYR61/Akt pathway	↑Autophagy, apoptosis. ↓Proliferation	Yin et al[31]
Wogonin	HepG2, BEL-7402	Modulate NF-κB/Bcl-2, EGFR and EGFR/ERK/AKT pathway	↓Proliferation	Liu et al[5]
	SMMC-7721, HCCLM3	↑MOB1-LATS1 pathway. ↓YAP, WW domain–containing transcription regulator 1, and expression of Claspin	↑Apoptosis, cell cycle arrest	Wu et al[32]
	MHCC97-L, HepG2	↑Phospho-GSK-3β Tyr216. ↓Cyclin D1	↑Cell cycle arrest. ↓Proliferation	Hong et al[33]
Baicalein	Human HCC tissues	Modulate lncRNAs-hsa-miR-4443-AKT1 pathway	↓Proliferation	Zhao et al[35]
Silibinin	HepG2, Hep3B	Modulate AMPK pathway	↑Autophagy. ↓Glycolysis	Yang et al[36]
	Huh7, HepG2, Hep3B, PLC/PRF/5 human hepatoma cells	↑p21/CDK4 and p27/CDK4 complexes. ↑Caspase-3 and -9. ↓Rb-phosphorylation and E2F1/DP1 complex	↑Apoptosis. ↓Proliferation	Lah et al[37]
luteolin	p53-wild type HepG2 cells, Hep3B	↑Endoplasmic reticulum stress	↑Autophagy, apoptosis	Lee and Kwon[38]
	HepG2	Modulate TGF-β1, p53, Fas/Fas ligand pathway	↑Apoptosis, cell cycle arrest	Yee et al[39]
	HepG2, SK-Hep-1, PLC/PRF/5, Hep3B, HA22T/VGH	↑Bax/Bcl-XL ratio. ↑Caspase-3	↑Cell cycle arrest	Chang et al[40]
Kaempferol	HepG2, Huh7, BEL-7402, SMMC	↑AMPK pathway. ↑Melanoma antigen 6, AMPK ubiquitin ligase, AMPKα1	↑Autophagy	Han et al[41]
Luteolin and Kaempferol	DEN and 2-AAF induced rat model	↑Caspase-3 and ROS reaction	↑Apoptosis	Seydi et al[42]
Quercetin	HepG2	↑p53, BAX. ↓ROS, PI3K, COX-2, PKC	↓Proliferation	Maurya and Vinayak[43]
Chlorogenic acid	Hep-G2, Huh7	↑BH3-only protein Bcl-2 binding component 3. ↓Noncanonical NF-κB pathway	↑Apoptosis	Jiang et al[45]
Thymoquinone	Thioacetamide (TAA)-induced HCC, Sprague Dawley rats	↓Oxidative stress. ↓TGF-β1	↑Apoptosis	Helmy et al[47]
Juglanthraquinone C	HepG2, BEL-7402	↑Akt/Fox O pathway. ↑Intracellular ROS level	↑Apoptosis	Hou et al[48]
4-acetylantrocamol LT3	HepG2	↑AMPK pathway	↑Autophagy	Chen et al[49]
Aloin	--	Modulate circ_0011385/miR-149-5p/WT1 axis	↑Apoptosis and autophagy	Fu et al[50]
Andrographolide	Hep G2	↓EphB4	↑Apoptosis	Duan et al[51]
Sanguisorba Officinalis L.	HepG2 cells	Modulate EGFR, PI3K/AKT, NF-κB and MAPK pathways	↓Proliferation	Jiang et al[52]
Plantamajoside	Huh7, PLC/PRF 5, THLE-2	↓NF-κB and Cox-2	↓Proliferation	Luo et al[53]

Akt: Protein kinase B; AMPK: AMP-activated protein kinase; Bax: BCL2-Associated X Protein; Bcl-2: B-cell lymphoma 2; CDK: Cyclin-dependent kinases; COX-2: Cyclooxygenase-2; EGFR: Epidermal growth factor receptor; EPHB4: EPH Receptor B4; ERK: Extracellular signal-regulated kinase; FoxO: Forkhead box O; GSK: Glycogen synthase kinase; JNK: c-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinase; Mst1: Mammalian sterile 20-like kinase 1; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa B; NOD: Nucleotide-binding oligomerization domain; PI3K: Phosphatidylinositol 3-kinase; PINK1: PTEN-induced kinase 1; PTEN: Phosphatase and tensin homolog deleted on chromosome 10; ROS: Reactive oxygen species; Skp2: S-phase kinase-associated protein 2; TGF: Transforming growth factor; TNFR: Tumor necrosis factor receptor; VEGF: Vascular endothelial growth factor; WWOX: WW domain-containing oxidoreductase; YAP: Yes-associated protein; DEN: Diethylnitrosamine; 2-AAF: 2-acetylaminofluorene.