Table 2.
Regulatory Impacts of THM compounds for HNSCC Cell Mobility/Metastasis and Angiogenesis.
| Herbal Compounds | Cell Types | Cellular/Molecular Changes | |
|---|---|---|---|
| Andrographis paniculata | EC-109 (Human esophageal squamous carcinoma) |
↓WNT/BMP pathway ↓ErbB and MAPK pathway [45] ↓TM4SF3, HER2, CXCR4, NFκB, MMP-2 and MMP-9 [46] |
|
| ## Intraperitoneal EC-109 xenograft mouse | ↓liver and lung metastases [46] ↓tumor weight and tumor nodule number [47] |
||
| Andrographispaniculate extract/isoandrographolide | EC-109/KYSE-520 (Human esophageal squamous carcinoma) HMEC-1 (Human microvascular endothelial cell) |
↓anoikis resistance, TM4SF3 [47] | |
| Eclipta prostrata | HSC-3/SCC-9 (Human tongue squamous carcinoma) TW2.6 (Human buccal carcinoma) |
↓MMP-2 (probably via ERK1/2 signaling pathways) [48] |
|
| Rubus Idaeus | SCC-9/SAS (Human tongue squamous carcinoma) |
↓MMP-2 (probably via ERK1/2 signaling pathways) [49,50] |
|
| HONE-1, NPC-39 and NPC-BM (Human nasopharyngeal carcinoma) | |||
| Selaginella tamariscina | HSC-3 (Human tongue squamous carcinoma) |
↓MMP-2 and MMP-9 ↑TIMP-1 and TIMP-2 (probably via Akt pathway) [51] |
|
| Duchesnea indica | SCC-9/SCC-14 (Human tongue squamous carcinoma) TW2.6 (Human buccal carcinoma) |
↓MMP-2 (probably via MEK/ERK1/2 signaling pathways) [52] |
|
| Leucaena leucocephala | SCC-9/SAS (Human tongue squamous carcinoma) |
↓MMP-2 (probably via ERK1/2 and p38 signaling pathways) [53] |
|
| Physalis angulata | HSC-3 (Human tongue squamous carcinoma) |
↓VEGF, MMP-2, MMP-9 and u-PA ↑TIMP-1, TIMP-2, PAI-1 and PAI-2 |
|
| HUVECs | In vitro | ↓MMP-2 | |
|
## In vivo (CAM assay) |
↓Induced neovascularization [54] | ||
| Galium verum | Hep-2/HLaC79 (Taxol sensitive/resistant human laryngeal carcinoma) |
↓MMP-2 [55] | |
| Rheum palmatum L. | SCC-9/SAS (Human tongue squamous carcinoma) |
↓MMP-2 (probably via ERK1/2 signaling pathways) [56] |
|
| Rheum palmatum L./Emodin, aloe-emodin and rhein | SCC-4 (Human tongue squamous carcinoma) |
↓MMP-2 and u-PA [57] | |
| Rheum palmatum L./Chrysophanol | FaDu (Human hypopharynx squamous cell carcinoma) SAS (Human tongue squamous carcinoma) |
↓EMT (↑E-cadherin, ↓vimentin) [31] | |
| Rhizomacoptidis/Berberine | SCC-4 (Human tongue squamous carcinoma) |
↓MMP-2, MMP-9, and u-PA [58] | |
| Gynostemmapentaphyllum Makino/Gypenosides | SAS (Human tongue squamous carcinoma) |
↓MMP-2, MMP-7, and MMP-9 [59] | |
| Myrtaceae pollen and Eucalyptus honey/Tricetin | SCC-9/HSC-3 (Human tongue squamous carcinoma) OECM-1 (Human oral epidermal carcinoma) |
↓MMP-9 (probably via p38/JNK1/2 pathway) [60] |
|
| Pinussylvestris/pinosylvin | SAS/SCC-9/HSC-3 (Human tongue squamous carcinoma) |
↓MMP-2 ↑TIMP-2 (probably via ERK1/2 signaling pathways) [61] |
|
| Salvia miltiorrhiza (Danshen)/salvianolic acid A | SCC-9/SCC-25 (Human tongue squamous carcinoma) |
↓MMP-2 (probably via c-Raf/MEK/ERK pathway) [62] |
|
| Quercetin (found in onion) | SAS (Human tongue squamous carcinoma) |
↓MMP-2 and MMP-9 [63] | |
| Phenethyl isothiocyanate | SAS (Human tongue squamous carcinoma) |
↓p-EGFR, MMP-2 and MMP-9 ↑TIMP-1 and TIMP-2 (probably via PI3K/AKT, NF-κB, and MAPK pathway) [64] |
|
| Gallic Acid | NPC-BM1 (Human nasopharyngeal carcinoma) |
↓MMP-1 ↑TIMP-1 (mediated by ↓AP-1, ETS-1, p-p38, c-fos and c-jun) [65] |
|
| Evodiamine | HONE1 (poorly differentiated) and CNE1 (well differentiated) (Human nasopharyngeal carcinoma) |
↓MMP-2 (probably via ↓NF-κB p65, p-ERK1/2) [66] |
|
| Ursolic acid (UA) | Ca922 (Human oral squamous cell carcinoma) |
↓angiogenesis ↓migration/invasion by blocking MMP-2 secretion [23] |
|
| Nobiletin | HONE-1 (Human nasopharyngeal carcinoma) NPC-BM (Human nasopharyngeal carcinoma derived from bone marrow metastatic lesion) |
↓MMP-2 ↑TIMP-2 (probably via ERK1/2, NF-kB, and AP-1 pathway) [67] |
|
| ## HONE-1 injected s.c. into the right flank of BALB/c nude mouse | ↓lung metastasis (↓NF–κB) [67] | ||
| Resveratrol | SCC-9 (Human tongue squamous carcinoma) |
↓MMP-9 (probably via JNK1/2 and ERK1/2 pathways) [68] |
|
| Triptolide | CNE (Human nasopharyngeal carcinoma) |
anti-angiogenesis [40] | |
| KYSE180 (well differentiated) Eca109 (well differentiated) KYSE150 (poor differentiated) (Human esophageal squamous carcinoma) |
differentially regulates metastasis [17,69] | ||
| Pinostilbene hydrate (methylated derivative of resveratrol) | SAS/SCC-9/HSC-3 (Human tongue squamous carcinoma) |
↓MMP-2 (probably via p38/ERK1/2 pathway) [70] |
|
| Epigallocatechin gallate (EGCG) | TW01 (Human keratinizing squamous cell carcinoma) TW06 (Human undifferentiated nasopharyngeal carcinoma |
↓stem cell genes (Oct4 and Klf4) ↓EMT related protein (↓Snail, Vimentin/↑E-Cadherin) [71] |
|
| TW01 (EBV-negative)/NA (EBV-positive), (Human nasopharyngeal carcinoma) NP460hTert (Human immortalized human nasopharyngeal cell) |
↓MMP-2 and MMP-9 (mediated by ↓ERK, AP-1 and Sp1 [72] | ||
| CNE2 and C666-1 (Human nasopharyngeal carcinoma) |
↓EMT (via NF-κB p65 inactivation) [73] | ||
| ## CNE2-SC xenograft nude mouse (combined with cisplatin treatment) | ↓N-cadherin, vimentin, Bmi-1, Twist1, and NF-κB p65 ↑E-cadherin [73] |
||
| CAL-27 (HNSCC cell) (treated alone or combined with Gefitinib) |
↓MMP-2, p-EGFR ↑TIMP-2 (probably via MAPK pathway) [74] |
||
| Qigesan (fufang) | TE1, TE13 and Eca109 (Human esophageal cancer) |
↑Cx26 and Cx43 [75] | |
| Fuzheng Yiliu granules |
&& Randomized clinical treatment (treatment group = 30, control group = 33) (combined with radiotherapy) |
↑RBC-C3bRR ↓RBC-ICRR and CD44v6 [76] |
|
| Aidi injection | EC9706/KYSE70 (Human esophageal squamous carcinoma) |
↓VEGF-A, cadherin-2 and vimentin ↑cadherin-1 [77] |
|
| ## EC9706 cells inoculated into the peritoneal cavity of BALB/c NU mouse | ↓vimentin and VEGF-A ↑cadherin-1 [77] |
||
##: In vivo study. &&: Clinical study. Abbreviations: MMP = metalloproteinase; u-PA = urokinase-type plasminogen activator; Cx = connexin; VEGF = vascular endothelial growth factor; TIMP = tissue inhibitor of matrix metalloproteinase; ERK = extracellular signal-regulated kinase; MAPK = mitogen-activated protein kinase; JNK = c-Jun N-terminal kinase (JNK); BMP = bone morphogenetic protein; TKI = tyrosine kinase inhibitor; EGFR = epidermal growth factor receptor; HIF-1α = Hypoxia inducible factor 1, alpha subunit; THBS2 = Thrombospondin 2; TGF = Transforming Growth Factor; AP-1 = activator protein-1; NF-κB = nuclear factor-κB; PAI = plasminogen activator inhibitors; HUVECs = human umbilical vein endothelial cells; CAM = chick chorioallantoic membrane; EBV = Epstein-Barr virus; ETS-1 = proto-oncogene 1.