Roles of conventional and complementary therapies in recurrent hepatocellular carcinoma

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.