Roles of Therapeutic Bioactive Compounds in Hepatocellular Carcinoma

Table 2

Bioactive compounds and their anticancer effect on hepatocarcinoma.

S. no.	Phytomolecules	Animal/cell lines	Methods	Chemical structure	Mechanisms	Ref.
1.	Andrographolide (labdane diterpene)	Swiss albino mice	In vivo (diethylnitrosamine) antioxidant assay		1. Liver biochemical parameters; 2. Increased MDA and NO level; 3. Decreased level of Gal-3 and IL-6	[130]
2.	Allicin (organosulfur compound)	HCC xenograft tumors in nude mice	In vivo		1. Increased intracellular ROS level; 2. Reduced MMP; 3. Activated caspase-3 and PARP; 4. Downregulated Bcl-2	[131]
3.	Aloe emodin (antraquinone)	HepaRG cells	MTT assay, annexin V-FITC/PI		1. Significant reduction in cell viability after treatment; 2. Induction of apoptosis in HepaRG cell line; 3. Provoked ROS generation; 4. Depolarization of MMP; 5. Induced cell cycle in S-phase; 6. Increases the level of mitochondrial cytochrome C, Fas, p21, Bax/Bcl2, and p53	[132]
4.	Arbutin (glycosylated hydroquinone)	Mice	In vivo (X-ray irradiation)		Liver biochemical parameters like ALP, ALT, and AST were significantly reduced	[133]
5.	Berberine (benzyl-isoquinoline alkaloid)	Hep3B, BEL-7404	Cell counting kit-8 assay and EdU assay		It suppressed the glutamine uptake by inhibiting SLC1A5	[134]
6.	Boldine (alkaloid)	Wistar rat	In vivo (diethylnitrosamine)		1. It induced the apoptosis; 2. Upregulate the protein expression of Bax and cleaved caspase 3	[135]
7.	Betulinic acid (triterpene)	NOD/SCID mice, HepG2, LM3, MHCC97H	MTT assay, pulmonary metastasis model		1. Induction of apoptosis; 2. Increased the Bax and cleaved caspase-3; 3. Decreased the level of Bcl-2; 4. Decreased the level of ROS; 5. Inhibit metastasis via MMP-2, MMP-9, and TIMP2	[136]
8.	Capsaicin (homovanillic acid alkaloid)	SCLC (NCI-H69, NCI-H82, DMS53, DMS114), chicken eggs	MTT assay, BrdU and PCNA proliferation assays, CAM assay, nude mice models, Chromatin immunoprecipitation (ChIP) assay		1. Decreased expression of E2F-responsive proliferative genes (cyclin E, thymidylate synthase, cdc25A, and cdc6, both at mRNA and protein levels); 2. G1 phase arrest	[137]
9.	Caffeine (purine alkaloid)	HepG2, HLF, Huh7, PLC/PRF/5	Hoechst 33258 staining, MAPK activity, flow cytometry		1. Inhibited the cell proliferation; 2. Activated the MERK-regulating kinase and ERK pathway; 3. Downregulation of EGRF	[138]
10.	Crocin (apocarotenoid)	Male albino, Wistar rats, HepG2	In vivo (DEN) induced hepato-carcinogenesis		1. Antiproliferative; 2. Induced proapoptotic body; 3. Arresting the cell cycle at S and G2/M phases; 4. Induced apoptosis	[139]
11.	Coumarin-6-sulfonamides (sulfonamide derivative)	HepG2	Sulforhodamine B (SRB) method, annexin V–FITC apoptosis assay		1. Induced apoptosis; 2. Upregulation of the Bax; 3. Downregulation of the Bcl-2; 4. Increased caspase-3 levels; 5. Arrest in the G2-M phase	[140]
12.	Carnosic acid (polyphenolicditerpene)	B16F10 cell xenograft model	MTT assay, BrdU incorporation assay		1. Arrested G0/G1 phase; 2. Enhances p21 expression; 3. Reduces the values of AST and ALT	[141]
13.	Curcumin (diarylheptanoid)	Liver cancer stem cells (LCCs), HepG2	MTT assay, Western blot analysis		1. Inhibited cell proliferation; 2. Induced apoptosis; 3. Inhibited the activation of the PI3K/AKT/mTOR signaling pathway	[142]
14.	Daidzein (7-hydroxyisoflavones)	SK-HEP-1	TUNEL assay		1. Increased expression of prdx-3; 2. Decreased ROS level; 3. Upregulation of Bak protein; 4. Downregulation of Bcl-2 and BclxL proteins; 5. Increased the release of mitochondrial cytochrome c; 6. Activated the APAF-1, caspase 9, and caspase 3	[143]
15.	Embelin (benzoquinone)	Male Swiss mice, Wistar albino rats, Sprague Dawley rats	In vivo (N-nitrosodiethylamine, CCl4)		1. Decreased incidence of preneoplastic foci; 2. Decreased biochemical markers (SGOT, SGPT, ALP, GGT, GST, and LPO)	[144]
16.	Esculetin (coumarin derivative)	C57BL/6J mice; Hepa1-6 cells	In vivo MTT assay		1. Inhibited proliferation of HCC cells; 2. Arrest cell cycle at S phase; 3. Induced apoptosis; 4.Increased caspase-3 and caspase-9 activity; 5. Increased Bax expression; 6. Decreased Bcl-2 expression	[145]
17.	Emodin (anthraquinone)	HepG2; Hep3B; Huh7; SK-HEP-1; PLC/PRF5	Western blotting, quantitative real-time PCR, tumor xenograft assay, Ki67 cell proliferation assay, annexin-V staining, luciferase assay		1. Attenuated cholesterol synthesis and oncogenic AKT signaling; 2. Inactivated STAT3; 3. Cell cycle arrest in the G1 phase	[146]
18.	Emodinsuccinylester (trihydroxyanthraquinone derivative)	BALB/c nu/nu athymic nude mice, Hep3B, Huh7	Western blot, quantitative RT-PCR, xenograft mouse model		1. Inhibited HCC cell proliferation and migration; 2. Decreased transcription level and protein expression of androgen receptor; 3. Enhanced of zeste homolog 2	[147]
19.	(-)-Epigallocatechin-3-gallate (catechin)	Mice, Hep3B, He-pG2, SK-hep1, HCC-LM3, Huh7, SMMC7721	Western blot analysis, cell viability analysis, tumor xenograft in nude mice model		1. Inhibited Hep3B cells by both antiproliferation and proapoptosis; 2. ERα36-EGFR-Her-2 feedback loop, PI3K/Akt, and MAPK/ERK pathways were inhibited	[148]
20.	Genistein (isoflavone)	Hepa1-6 cell line	Cell viability assay, Flow cytometry		1. Inhibited the growth of Hepa1-6 cells; 2. Induced apoptosis	[149]
21.	Gallic acid (phenolic acid)	Wistar albino rats	In vivo (diethylnitrosamine)		1. Decreased the size of tumors; 2. Decreased the levels of marker enzymes in serum; 3. Decreased the levels of AgNORs and PCNA	[150]
22.	18𝛽-Glycyrrhetinic acid (triterpene)	HepG2, H22	MTT assay		Decreased cell viability in higher concentration	[151]
23.	Hesperidin (flavonoid)	HepG2 cells	MTT assay, DAPI staining		1. Induced cell death; 2. Activated mitogen-activated; 3. Protein kinase ERK1/2; 4. Inhibited cell proliferation; 5. Arrested G1 phase cells; 6. Induced proptosis like cell death; 7. Induced depletion of MMP	[152]
24.	Honokiol (biphenol neolignans)	CCA cell lines (KKU-100 and KKU-213)	MTT assay		1. Inhibited cell proliferation; 2. Arrested G0/G1 cell cycle phase; 3. Induced apoptosis; 4. Suppressed the adhesion and migration of cell; 5. Inhibited the MMP-9 and MMP-2 activity	[153]
25.	Kaempferol (Flavonoid)	HepG2 cell	Cell counting kit-8 assay, BrdU incorporation assay, Guava Nexin assay, two-chamber migration (invasion) assay		1. Inhibited cell proliferation, migration, and invasion; 2. Induced cell apoptosis; 3. Reduce the expression of miR-21; 4. Enhanced the expression of PTEN; 5. Inactivated PI3K/AKT/mTOR signaling pathway	[154]
26.	Lupeol (triterpene)	MHCC-LM3, nude mice (BALB/c-nu/nu)	MTT assay, xenograft model		1. Inhibited in vivo tumorigenicity; 2. Downregulated CD133 expression; 3. Sensitize (PTEN)-Akt-ABCG2 pathway	[155]
27.	Magnolol (lignan)	HepG2 cells, nude mice (Balb/c nu/nu)	MTT assay, Transwell assays, flow cytometric analysis		1. Inhibited the proliferation, migration, and invasion of cells; 2. Induced apoptosis; 3. Induction of ER stress; 4. Release of cytochrome C; 5. Arrested S-phase; 6. Suppressed tumor growth in vivo	[156]
28.	Mangiferin (xanthone glucoside)	Male Swiss albino mice	In vivo (lead-induced) MTT assay		1. Decreased ROS formation; 2. Restored the MMP; 3. Regulation of Bcl-2/Bax; 4. Inhibited activation of MAPKs (phospho-ERK 1/2, phosphor-JNK phospho- p38); 5. Induced apoptosis	[157]
29.	Naringenin (trihydroxyflavanone)	HepG2 cells	Flow cytometry; Cell viability assay		1. Inhibited the cell proliferation; 2. G0/G1 and G2/M phase arrest; 3. Induced apoptosis; 4. Increased ratio of Bax/Bcl-2; 5. Release of cytochrome C; 6. Activation of Caspase 3	[158]
30.	Oleuropein (monoterpenoid)	HepG2, Huh7	Cell counting kit 8, flow cytometric analysis, cell viability assay, luciferase assay		1. Suppressed expression of activated AKT; 2. Inhibited cell growth; 3. Induced cell apoptosis; 4. Inhibited PI3K/AKT signaling pathway	[159]
31.	Oleanolic acid (triterpenoid)	HepG2	MTT assay, cell viability assay, annexin V-FITC		1. Induced cytotoxic effect; 2. G0/G1 cell cycle arrest; 3. Reduced MMP	[160]
32.	Parthenolide (sesquiterpene lactone)	HepG2	MTT assay, DAPI, TUNEL staining, Western blotting, monodansylcadaverine (MDC), AO staining		1. Increased the number of apoptotic nuclei; 2. Reduced expression of Bcl-2; 3. Increased expression of Bax, p53, and caspase-3 and 9; 4. Induced autophagy; 5. Inhibited the expression of the Ki-67 gene	[161]
33.	Phycocyanin (phycobiliproteins)	NSCLC (A549, NCI-H1299, NCI-H460, and LTEP-A2)	MTT assay, annexin V-FITC and 7AAD staining		1. Induced apoptosis; 2. Regulated the NF-kB signaling of NSCLC cells; 3. Significantly reduced the expression of MMP-2 and MMP-9; 4. Suppressed the proliferation of NSCLC cells; 5. Arrested G1 and S phase of cell cycle	[162]
34.	Quercetin (flavonoid)	HCC (LM3), nude mice model	Flow cytometry, TUNEL assay, qRT-PCR, Western blotting		1. Suppressed cell viability; 2. Induced cell apoptosis; 3. Inhibited the activation of the JAK2/STAT3 pathway; 4. Inhibited cell migration and invasion; 5. Inhibited tumor growth in nude mice model	[163]
35.	Rutin (flavonoid)	HepG2 cell line	Diamino-benzoic acid and bromodeoxyuridine assays, lactate dehydrogenase leakage assay, fluorimetric assay, dichlorofluorescein assay, northern blot		1. Decreased ROS and MDA concentration; 2. Arrested cell growth at higher concentration; 3. No cytotoxic effect on HepG2 cells	[164]
36.	Rosmarinic acid (coumaric acid derivative)	H22 tumor-bearing mice	ELISA, Western blotting, qRT-PCR		1. Decreased p65 phosphorylation; 2. Inhibited the tumor growth; 3. Decreased the elevated level of cytokines	[165]
37.	Resveratrol (polyphenol)	HepG2	MTT assay, flow cytometric analysis, Western blot analysis, laser confocal microscopy		1. Inhibited cell proliferation; 2. Arrested G1 phase; 3. Downregulated the expression of cyclin D1, p38 MAP kinase, Akt, and Pak1; 4. Increased ERK activity; 5. Induced apoptosis	[166]
38.	Salidroside (p-hydroxy-phen-ethyl-β-d-glucoside)	Human hepatocellular carcinoma (HHCC)	MTT assay, Western immunoblotting		1. Inhibited cell proliferation; 2. Arrested G2 phase; 3. Inhibited CDK-cyclin activity	[167]
39.	Ursolic acid (pentacyclictriterpenoid)	HepG2, Hep3B	Cytotoxicity assay, ethidium homodimer assay, deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, cell cycle analysis, Western blotting		1. Enhanced the expression of PARP and Caspase3; 2. Increased the sub-G1 population; 3. Attenuated the expression of AEG1gene; 4. Increased the phosphorylation of AMPK, GSK3β, and coenzyme A; 5. Attenuated the phosphorylation of AKT and mTOR	[168]
40.	Withaferin A (steroidal lactone)	Nude mice model, MHCC97, JHH-5	Xenogen in vivo imaging system, Western blot analysis, liquefied Matrigel assay		1. Inhibited the tumor growth; 2. Decreased intrahepatic metastasis; 3. Inhibited the expression of Pyk2, ROCK1 protein, and VEGF; 4. Suppressed the formation of actin projection	[169]
41.	Xanthatin (sesquiterpene lactone)	HepG2, Bel-7402, SMMC-7721	MTT assay, cell viability assay, flow cytometry, annexin-V/PI double staining assay, Western blotting, immunofluorescence staining, dual-luciferase reporter gene assay		1. Reduced cell viability; 2. Arrested S phase cell cycle; 3. Induced apoptosis; 4. Induced ERS and activated UPR pathway	[170]