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.

Table 2 Compounds and formulas for reducing hepatocellular carcinoma recurrence via inhibition of epithelial-mesenchymal transition, migration, invasion and metastasis

Compound or Chinese herbal medicine or formula	Cell line/animal/human	Molecular mechanism	Effect and outcome	Ref.
Astragaloside IV	Huh7, MHCC97-H	Modulate Akt/GSK-3β/β-catenin pathway. ↑E-cadherin. ↓N-cadherin, vimentin, α-Smooth Muscle Actin, Slug	↓EMT, invasion, migration	Qin et al[66]
Camptothecin	Huh7	Modulate ZO-1, E-cadherin, claudin-1	↓EMT, metastasis	Liu et al[57]
Isoviolanthin	HepG2, BEL-7402	↓TGF-β1. ↓TGF-β/SMAD and PI3K/Akt/mTOR pathway. ↓MMP-2 and -9	↓EMT	Xing et al[67]
18β-Glycyrrhetinic Acid	BEL-7402, LM3	Modulate. SHP1&SHP2/STAT3/Snail pathway. ↓Phosphorylation of STAT3. ↑SHP1 and SHP2	↓EMT and metastasis	Jie et al[68]
Echinacea purpurea	Hepa1-6, HepG2, L-02	Modulate PI3K/Akt pathway	↓EMT	Xu et al[69]
Tetrandrine	Huh7, Hep3B	↓Wnt/β-catenin pathway. ↓Metastatic tumor antigen 1	↓EMT, invasion, migration	Zhang et al[70]
Scorpion	Hepa1-6/Sprague-Dawley rats (6-wk, male, 0.63 g/200 g, every day for 4 wk)	↑E-cadherin. ↓N-cadherin	↓EMT, migration, invasion	Yan et al[71]
Myricetin	MHCC97-H	↑E-cadherin expression. ↓N-cadherin	↓Migration, invasion	Ma et al[72]
Hydroxygenkwanin	HepG2 and Huh7/nude mice (6-wk, male, 1 mg/kg for 3 times per week)	↑miR-320a, ↓Forkhead box protein M1	↓EMT, invasion, migration. ↓Tumor size	Chou et al[73]
Oleanolic acid	HepG2, SK-Hep-1	↑miR-122, E-cadherin. ↓β-catenin, N-cadherin, vimentin	↓EMT, migration, invasion	He et al[74]
Aloin	--	Modulate circ_0011385/miR-149-5p/WT1 axis	↓Invasion	Fu et al[50]
Puerarin	BEL-7402, Huh7, L-02	↑PTEN. Modulate miR-21/PTEN/EMT axis	↓EMT, migration, invasion	Zhou et al[75]
Corylin	Hep G2, Huh7/nude mice (BALB/cAnN-Foxnlnu/CrlNarl, 6-wk, male, 60 mg/kg, 3 times per week)	↑GAS5	↓EMT. ↓Tumor size	Chen et al[76]
Kaempferol	Huh7, SK-Hep-1	↓MMP-9 and Akt pathway	↓Migration	Ju et al[77]
Dulcitol	HepG2	↓MMP-2, uPA, MMP-9. ↑E-cadherin	↓Migration and invasion	Lin et al[78]
Sanguisorba officinalis	HepG2	Modulate EGFR, PI3K/AKT, NF-κB and MAPK pathway	↓Migration, invasion	Jiang et al[52]
Zanthoxylum avicennae	HA22T	↑PP2Acα, GSK-3β, APC, β-TrCP/HOS. ↓β-catenin, p-GSK-3β, TBX 3, IL-8. ↓Nuclear and cytosolic β-catenin	↓Metastasis	Wu et al[79]
Bufalin	MHCC97-H	↑TBK1, IRF3 and NF-κB pathway	↓Migration, invasion	Feng et al[80]
QHF (consisting of HuaChanSu, 20(R)ginseng saponin Rg3, notoginseng total saponin and lentinan)	HepG2	↑p38, JNK, MAPK pathway. ↓ERK pathway	↓Migration, invasion	Chen et al[81]
QHF (consisting of cinobufotalin, ginsenoside Rg3, panax notoginsenosides, lentinan)	HCCLM3, HepG2/SPF BALB/c mice (20 g, male, 0.2 ml/mice, once every other day for 4 wk)	↓p-c-Met protein. ↓HGF/c-Met pathway	↓Metastasis, invasion	Yuan et al[82]
Biejiajian pill	MHCC-97H, SMMC-7721/BALB/c nude mice (4-5 wk, female, 1.1 g/kg, daily for 4 wk)	↓Akt/GSK-3β/Snail pathway	↓EMT, metastasis	Sun et al[83]
Jiedu Recipe	SMMC-7721, Huh7	↑E-cadherin. ↓p-Smad2/3, Smad2/3. ↓TGF-β1, vimentin, N-cadherin, MMP2/9	↓EMT, invasion, migration	Liang et al[84]
Xiaoai Jiedu Recipe	Male nude mice (BALB/c (nu/nu), 4–5 wk, male, 10 g/kg, 4 consecutive days). 40 HCC patients and 40 volunteer controls	Modulate miRNA-29a signal transducer ↑Transcription 3 Axis	↓Metastasis	Shi et al[85]

Akt: Protein kinase B; EMT: Epithelial-mesenchymal transition; ERK: Extracellular signal-regulated kinase; FGFR: Fibroblast growth factor receptor; GAS5: Growth arrest-specific transcript 5; GSK: Glycogen synthase kinase; HCC: Hepatocellular carcinoma; HGF: Hepatocyte growth factor; IL: Interleukin; IRF3: Interferon regulatory factor 3; JNK: c-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinase; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa B; PI3K: Phosphatidylinositol 3-kinase; PP2Acα: α isoform of the catalytic subunit of protein phosphatase 2A; PTEN: Phosphatase and tensin homolog deleted on chromosome 10; SHP: Src homology 2 domain-containing protein tyrosine phosphatases; SMAD: Suppressor of Mothers against Decapentaplegic; STAT3: Signal transducer and activator of transcription 3; TBK1: Tank-binding kinase 1; TBX3: T-Box Transcription Factor 3; TGF: Transforming growth factor; ZO: Zonula Occludens Protein; APC: Adenomatous polyposis coli; β-TrCP: β-transducin repeat-containing protein.

Table 3 Compounds and formulas for reducing hepatocellular carcinoma recurrence via inhibition of cancer stemness

Compound or Chinese herbal medicine or formula	Cell line/animal	Molecular mechanism	Effect	Ref.
Antrodia cinnamomea	Hep G2	↓CD133+	↓CSC	Su et al[89]
Tiliroside	Hep3B, SNU-449	↓CD133+. ↓Carbonic anhydrases XII. ↑E2F1/E2F3/Caspase-3 axis	↓Tumor sphere formation. ↓WInvasion and migration. ↓Stemness gene expression. ↑Apoptosis	Han et al[90]
8-bromo-7-methoxychrysin	SMMC-7721, MHCC97H-derived LCSLCs	↓CD133, CD44. ↓IL-6	↓CSC	Wen et al[91]
Curcumin	PLC/PRF5, WRL68, Huh7, KMCH, AFP-negative primary HCC cell line	↓CD117, EpCAM, CD133, RNF51, NANOG. ↓NF-κB	↓CSC	Marquardt et al[92]
Sophocarpine	HCC-LM3, MHCC-97H. BALB/c nude mice (4-wk, male, 0.4-6 g/kg, twice a week for 4 wk)	↓TGF-β. ↓CD133, CD90 and EpCAM	↓EMT. ↓CSC	Zhang et al[93]
Matrine	Hep3B, Huh7. BALB/c nude mice (-,-,10 mg/kg, daily for 3 wk)	↓EpCAM+/CD133+ cell number. ↓PI3K/AKT/mTOR pathway, AKT/GSK-3β/β-catenin pathway	↓Sphere formation. ↓Stem cell markers. ↑Mature hepatocyte markers	Liu et al[94]
Brucea javanica	HepG2 (HB-8065, wild-type p53), Hep3B (HB-8064, p53-null)	↓CD133, NANOG, EpCAM	↑Apoptosis. ↓Stem-like cells	Chen et al[95]
2-Ethoxystypandrone	Hep3B, HepG2, Huh7, Li-7, SK-Hep-1	↓STAT3 activation	↓Proliferation, ↑Apoptosis. ↓CSC	Li et al[96]
BRM270	HepG2 (CD133+), SNU-398. CRJORI:CD-1-5WM (6-wk, male, 5 mg/kg/day, daily for 12 wk)	↓CyclinD1/Bcl2 mediated c-Jun apoptotic pathway. ↓CD113	↓Proliferation, ↑Apoptosis. ↓CSC	Kumar et al[97]
Songyou Yin (consisted by Salvia miltiorrhiza, Astragalus membranaceus, Lycium barbarum, Crataegus pinnatifida and Trionyx sinensis)	MHCC97-H, Hep3B	↓CD90, BCRP, ALDH, CD44, EpCAM, vimentin, MMP-9. ↑E-cadherin	↑Oxaliplatin chemosensitivity. ↓Motility, invasion, and colony formation. ↓CSC	Jia et al[98]

Akt: Protein kinase B; ALDH: Aldehyde dehydrogenases; Bcl-2: B-cell lymphoma 2; BCRP: Breast cancer resistant protein; CD: Cluster of differentiation; COX-2: Cyclooxygenase-2; EpCAM: Epithelial cell adhesion molecule; GSK: Glycogen synthase kinase; HIF: Hypoxia-Inducible Factor; IL: Interleukin; MMP: Matrix metalloproteinase; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa B; PI3K: Phosphatidylinositol 3-kinase; RNF51: RING finger protein 51; STAT3: Signal transducer and activator of transcription 3; TGF: Transforming growth factor; VEGF: Vascular endothelial growth factor.

Table 4 Compounds for reversing drug resistance

Compound or Chinese herbal medicine	Conventional drug	Cell line	Molecular mechanism	Ref.
Trametes robiniophila Murr	Oxaliplatin	BEL-7404, SMMC-7721	↓YAP and apoptosis related proteins	Tao et al[104]
Falcarindiol	Cisplatin	Huh7, LM3	↓STAT3/PTTG1 pathway	Hong et al[105]
Dihydroartemisinin	Doxorubicin	Mutant p53 (R248Q)-expressing Hep3B	Modulate p53 (R248Q)-ERK1/2-NF-κB pathway. ↓P-gp expression	Yang et al[106]
Solanum nigrum	Cisplatin and doxorubicin	Hep3B, HepJ5	↑Cleavage of caspase-7. ↑LC-3 A/B II. ↑Apoptosis, autophagy	Wang et al[107]
Bufalin	5-FU	BEL-7402/5-FU	↑Apoptosis arrested the cell cycle at the G0/G1 phase. ↑Bax/Bcl-xL ratio. ↓MRP1, thymidylate synthase (inhibit drug efflux pump activity)	Gu et al[108]
H1 (a derivative of tetrandrine, molecular formula: C27H40N2O6Br)	5-FU	BEL-7402/5-FU	↓STAT3/MCL-1 pathway. ↑PUMA expression	Li et al[109]
Artesunate	Sorafenib	SK-hep1, SMMC-7721	↑Apoptosis. ↓RAF/MAPK pathway. ↓PI3K/AKT/mTOR pathway	Jing et al[110]
Tetrandrine	Sorafenib	SMMC-7721, PLC/PRF/5	↓PI3K/AKT/mTOR pathway. ↓Proliferation. ↑Apoptosis	Niu et al[111]
Bufalin	Sorafenib	HepG2, Huh7	↓p-Akt. Modulate IRE1 pathway	Zhai et al[112]
Solamargine	Sorafenib	HepG2, Huh7	↓lncRNA HOTTIP and TUG1. Modulate HOTTIP-TUG1/miR-4726-5p/mucin 1 pathway	Tang et al[113]
8-bromo-7-methoxychrysin	Sorafenib	SMMC-7721	↓Migration and invasion. ↓N-cadherin. ↑E-cadherin ↑Apoptosis in LCSLCs. ↓HIF-1α and EMT regulator Twist1	Zou et al[114]
Icaritin	Doxorubicin and lenvatinib	Hepa1-6, Huh7	↑Mitophagy and apoptosis. ↑Immunogenic cell death	Yu et al[115]

Akt: Protein kinase B; Bax: BCL2-Associated X Protein; Bcl-xL: B-cell lymphoma extra- large; EMT: Epithelial-mesenchymal transition; ERK: Extracellular signal-regulated kinase; HIF: Hypoxia-Inducible Factor; HOTTIP: HOXA distal transcript antisense RNA; IRE1: Inositol-requiring enzyme 1; LC-3 A/B II: Microtubule-associated protein-1 light chain-3 A/1B II; LCSLC: Liver cancer stem-like cell; MCL-1: Myeloid cell leukemia 1; MRP1: Multidrug Resistance Protein 1; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa B; PI3K: Phosphatidylinositol 3-kinase; PTTG1: Pituitary tumor transforming gene 1; RAF: Rapidly accelerated fibrosarcoma; STAT3: Signal transducer and activator of transcription 3; TUG1: Taurine upregulated 1; YAP: Yes-associated protein; 5-FU: 5-fluorouracil.