Table 3.
In vitro Anticancer Effects and Mechanistic Insight of Licorice Bioactive Phytocompounds
| Type of Cancer | Cell Lines | Anticancer Effects | Mechanisms | Concentration | Reference |
|---|---|---|---|---|---|
| Melanoma | SK-MEL-28 and SK-MEL-5 | Induced apoptosis | ↓G1 phase, ↓cyclin D1, ↓cyclin E, ↓p-Akt, ↓p-GSK3β, ↓p-JNK1/2, ↓PI3K, ↓MKK4, ↓MKK7 | 10–20 μM | [46] |
| Glioma | C6 | Suppressed cell proliferation | ↓Cell viability, ↑cytotoxicity towards cancer cells, ↑antitumor activity, ↓cell number, ↑differentiated morphology, ↑reversion of tumor cells to the normal differentiated cells, ↓topoisomerase IIγ | 1, 10, 25, 50, 75, and 100 μM | [232] |
| Nasopharyngeal | C666-1 cells | lncRNA-regulated mechanism | ↓lncRNA, ↓AK027294, ↑production of EZH1, ↑caspase-3, ↑caspase-8, ↑caspase-9 | 0.25, 0.5, and 1 mg/mL | [233] |
| Nasopharyngeal | C666-1 | Induced apoptosis | ↑Antiproliferative properties, ↑apoptosis rate, ↑percentage of down-regulated amino acids and lipids leading to decreased metabolic disorders, ↓cell proliferation, ↓cell viability, ↑caspase-9 protease activities, ↑caspase-3 | 0.2, 0.5, and 1 mg/mL | [234] |
| Pharyngeal squamous | FaDu | Induced apoptosis | ↑Cytotoxicity towards cancer cells, ↑number of dead cancer cells, ↑chromatin condensation, ↑Fas, ↑cleaved caspase-8, ↑Bax, ↑apoptotic protease-activating factor 1, ↑caspase-9, ↑p53, ↓Bcl-2, ↑cleaved caspases-3, ↑cleaved PARP | 0,12.5,25 and 50 µg/mL | [202] |
| Adenoid cystic | ACC-2 and ACC-M | Induced autophagic and apoptotic cell death | ↓mTOR, ↑appearance of membranous vacuoles, ↑formation of acidic vesicular organelles, ↑punctate pattern of LC3 immunostaining, ↓autophagic flux, ↓apoptosis, ↓LC3- II/LC3-I ratio, ↓ cleavage of LC3, ↓autophagic flux, ↑caspase-3, ↑Bax/Bcl-2 ratio, ↑PARP-cleavage, ↓phosphorylated-S6 (downstream target of mTOR) | 5–20 µM | [235] |
| Colon | HT-29 | Induced apoptosis | ↓Proliferation, ↓viability of cells, ↑cell death of cancer cells, ↓HSP90 | 50,100,150, and 200 µg/mL | [236] |
| Non-small cell lung cancer | H1975 A549 | Inhibited metastasis | G0/G1 growth phase cycle arrest, ↓number of cells at both S growth phase and G2/M growth phase, ↓cyclin B1 and cyclin A2, ↓p21 (CDK inhibitor), ↑CDK2, ↑ESR1, ↑PPARG, ↑ESRRA, ↑PRKACA, ↑CXCL8, ↑PLAA, ↑RXRB, ↑MAPK14 levels of CDK4, ↓cyclin D1, ↓CDK4-Cyclin D1 complex | 200,400,600 and 800 μg/mL | [237] |
| Gastric | MKN28 | Inhibited metastasis | ↓Proliferation and metastasis, ↓migration and invasion, ↑LC3II/LC3I ratio, ↑Beclin 1, ↓p62, ↓p-Akt, ↓p- mTOR | 0,5,10,15 and 20 µM | [238] |
| Hepatocellular | MHCC97-H, LO2, and SMMC7721 | Induced apoptosis and autophagy | ↓Cell viability and proliferation, ↑apoptosis frequency, ↑Bax, ↑cleaved-caspase-3, ↑cleaved PARP, ↑endogenous LC3-II, ↓ Bcl- 2, ↓P62, punctate LC3, ↓p-Akt, ↓p-PI3K, ↓p- mTOR | 12.5, 25, and 50 μM | [239] |
| Hepatocellular | HuH7 and HepG2 | Induced autophagy | ↑Autophagosome number, ↑ROS generation, ↑TSC1/2 complex, ↑PRAS40, ↑ CTMP, ↑PP2A, ↑ PDK1 and ↑Rubicon ↑LC3 II, ↑cleaved-PARP, ↑cleaved-caspase-3 | 10,20,50,100 μM | [240] |
| Renal | Caki | Induced apoptosis | ↑Cleavage of caspase-9, caspase-7 and caspase-3, and PARP, ↑Bax, ↓Bcl-2, ↓ Bcl-xL, ↑cyt. c release, ↑p53, ↓MDM2, ↑ROS levels, ↓STAT3, ↓cyclin D1 and D2, ↓p-JAK2, | 0,5,10,20 and 50 µM | [138] |
| Breast | MDA-MB-231 triple negative | Induced apoptotic and autophagic-mediated apoptosis | ↓Cell cycle progression, ↓cyclin D1, ↑sub-G1 phase population, ↓Bcl-2, ↑ Bax, ↑caspase-3, ↑PARP, ↓mTOR, ↓p-mTOR ↓ULK1, ↓cathepsin B, ↑p62, ↑Beclin1, ↑ LC3, ↑caspase-8 | 10, 25 and 50 µM | [241] |
| Breast | MDA-MB-231 | Induced apoptosis | ↓Cell migration, ↓cell proliferation, ↑ mitochondrial membrane potential, ↑DNA damage, ↓ oxidative stress, ↑cleaved-caspase 3 and 9, ↓Bcl-2 expression, ↑E-cadherin ↓Vimentin, ↓N-cadherin, ↑release of cytochrome c from the mitochondria into the cytoplasm, ↑ROS | 30–40 µM | [242] |
| Breast | MDA-MB-231 | Exerted anti-inflammatory and antitumorigenic effects | ↓NO production, ↓iNOS, ↓LPS/IFN-γ, ↑NF κB, ↑ERK, ↑miR-155, ↓bound p50 and p65 | 10,50,100 and 200 μM | [243] |
| Breast | MCF-7 | Induced apoptosis | Cell cycle arrest in the G1 phase, ↓Bcl-2, ↑Bax, ↓cyclin D1, ↑PARP cleavage, ↑CIDEA | 15, 10, and 5 µg/mL | [244] |
| Breast | MCF-7 | Induced apoptosis | ↓Cell viability and proliferation, ↑apoptosis frequency, ↑TFF1 (pS2), ↑CTSD, ↑CDKN1A (an effector of p53), ↑RPS6KA (RSK; MAPK-related) ↑NRIP1 (RIP140, AP-1-related), ↓TP53I11 (p53- related), ↓PRKCD ↓ARHGDIA (a Ras super-family gene) | 0.1–100 μM | [245] |
| Murine mammary | 4T1 and MCF-10A | Inhibited metastasis | ↓Tumor growth, cell proliferation, ↓VEGF-A, ↓CD31 ↓HIF-1α, ↓iNOS, ↓COX-2 | 0,1,2.5 and 5.0 µg/mL | [246] |
| Bladder | T24 | Induced apoptosis | ↑Nuclear condensation, ↑ nuclear fragmentation, ↑ apoptotic ratio, ↑decrease in the ΔΨ m, ↑Bax, ↑ Bim, ↑Apaf-1, ↑caspase-9, ↑caspase-3, ↓Bcl-2, ↑CDK2 | 10,20,30,40,5, 60.70 and 80 µg/mL | [247] |
| Bladder | T24 | Induced apoptosis | ↓Proliferation, ↑ROS,↑apoptosis frequency, ↑mitochondrial dysfunction, ↑caspase-3, ↑PARP cleavage, ↑ER stress; GRP 78, ↑growth arrest, ↑DNA damage-inducible gene 153/C/EBP homology protein (GADD153/CHOP) expression, ↑caspase-12 | 20, 40, 60, 80, or 100 µM | [248] |
| Endometrial | HEC-1A, Ishikawa, and RL95-2 | Inhibited metastasis | ↓Survival rate of cancer cells, ↓N-cadherin, ↑E-cadherin | 1, 5, 10, and 20 µM | [182] |
| Endometrial | Ishikawa, HEC-1A, and RL95-2 cells | Induced apoptosis and autophagy | ↓Viability of cancer cells, ↑sub-G1 or G2/M phase arrest, ↑DNA damage, ↑cell cycle arrest, ↑apoptotic cell death, ↑cleaved caspase-3, ↑cleaved PARP, ↑caspase-7/LC3BII, ↑p-ERK, ↑LC3-II, ↑SQSTM1/p62 levels | 5, 10, 25, 50, 75, and 100 μM | [249] |
| Prostate | PC-3 | Induced apoptosis and autophagy | ↓Proliferation, G0/G1 cell cycle arrest, ↑apoptotic effect, ↑necrosis percentage, LC3B-II protein, ↑LC3B-II/LC3B-I ratio, ↑LC3A, ↑mRNA level ULK1 and AMBRA1, ↑NBR1 and p62 | 3–200 μg/mL glycyrrhiza extract + 3–100 nM Adriamycin | [250] |
| Ovarian | OVCAR5 and ES-2 | Induced apoptosis | ↓Viability of cancer cells, ↑G2/M phase arrest, ↑cleaved PARP, ↑cleaved caspase-3, ↑Bax/Bcl-2 ratio, ↑LC3B-II, ↑Beclin-1 | 1, 5, 10, 20, 25, 50, 75, and 100 µM | [251] |
| Cervical | SiHa, HeLa, HK 2 | Induced autophagy and apoptosis | ↓Viability of cancer cells, ↑cleaved-caspase-3, ↑cleaved caspase-9, ↑cleaved-PARP, ↓Bcl-2, ↑LC3-II, ↑Beclin1, ↑Atg5, ↑Atg7 ↑ Atg12, ↓PI3K (p85), ↓p-Akt (ser473), ↓p-mTOR (ser2448), ↓p-mTOR (ser2481) | 10, 30, and 50 µM | [252] |
| Osteosarcoma | Saos-2 | Induced apoptosis | ↓Proliferation, ↓cell migration, ↓cyclin D1, ↑p53, ↑p21, ↑p27, ↓Bcl-2, ↑Bax, ↓level of ATP-synthesis, ↓ PI3K/Akt signaling, ↓MMP2, ↓MMP9 | 0,3,10,30, and 100 µM | [253] |
| Osteosarcoma | U2OS | Induced apoptosis | ↓Proliferation, ↓invasion and migration, ↑apoptosis, ↑Bax, ↑active caspase-3, ↓Bcl- 2, ↓p-Akt, ↓p-mTOR, ↓PI3K/Akt signaling pathway | 5, 10 and 20 µM | [254] |
Abbreviations: AMBRA1, activating molecule in Beclin-1-regulated autophagy protein 1; AP-1, activator protein 1; Apaf-1, apoptotic protease activating factor-1; ARHGDIA, Rho GDP dissociation inhibitor alpha; Atg, autophagy related; ATP, adenosine triphosphate; Bax, BCL2 associated X; BCL-2, B-cell lymphoma 2; CD31, cluster of differentiation 31; CDK, cyclin dependent kinase; CDKN1A, cyclin dependent kinase inhibitor 1A; CHOP, CCAAT/enhancer-binding protein (C/EBP) homologous protein; CIDEA, cell death activator; COX-2, cyclooxygenase-2; CTMP, carboxyl-terminal modulator protein; CTSD, cathepsin D; CXCL, chemokine (C-X-C motif) ligand; DNA, deoxyribonucleic acid; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; ESR1, estrogen receptor 1; ESRRA, estrogen related receptor alpha; EZH-1, enhancer of zeste 1 polycomb repressive complex 2 subunit; GADD, growth Arrest and DNA damage inducible protein 153; GRP78, glucose-regulating protein; HIF-1α, hypoxia inducible factor 1α; HSP, heat shock protein; IFN-γ, interferon- γ; IL, interleukin; iNOS, inducible nitric oxide synthase; LC3, microtubule-associated protein 1A/1B-light chain 3; lncRNA, long non-coding RNA; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; miR, microRNA; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; mRNA, messenger ribonucleic acid; mTOR, mammalian target of rapamycin; NBR1, neighbour of BRCA1 gene; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; NRIP1, nuclear receptor-interacting protein 1; p-Akt, phospho-Akt; PARP, poly (adenosine diphosphate-ribose) polymerase; PDK1, phosphoinositide-dependent kinase 1; p-ERK, phospho-extracellular signal-regulated kinase; p-GSK3β, phospho-glycogen synthase kinase-3β; PI3K, phosphoinositide 3-kinase; p-JNK, phospho-c-Jun N-terminal kinase; PLAA, phospholipase A2-activating protein; PP2A, protein phosphatase 2A; PPARG, peroxisome proliferator-activated receptor gamma; PRAS, proline-rich Akt substrate; PRKACA, protein kinase CAMP-activated catalytic subunit alpha; PRKCD, protein kinase C delta; RIP140, receptor-interacting protein 140; ROS, reactive oxygen species; RPS6KA, p90 ribosomal S6 kinase-3; RSK, ribosomal S6 kinase; RXRB, retinoid X receptor beta; SQSTM1, sequestosome 1; STAT3, signal transducer and activator of transcription 3; TFF1, trefoil factor 1; TP53, tumor protein p53; TSC, tuberous sclerosis complex; ULK1, Unc-51-like autophagy activating kinase 1; VEGF-A, vascular endothelial growth factor A; ΔΨ, mitochondrial membrane potential.