Table 4.
Natural products modulating ROS in chemo-/radiotherapy of HNC.
| Category | Herb | Site | Experimental model | Effective dose | Cotherapy | ROS detection | Biological effect | Mechanisms | Reference |
|---|---|---|---|---|---|---|---|---|---|
| Flavonoids | Quercetin | Larynx | In vitro (Hep2 cell) |
40 μM | +Cisplatin (2.5 μg/ml) |
— | Synergistic effects | ↓Cu/Zn SOD, ↓p-AKT, ↑p-JNK, ↑c-FOS, ↓Bcl-2, ↓Bcl-xL, ↓survivin, ↑Bax, ↑cytochrome c, ↑caspase-3, ↑caspase-9, ↓NOS, ↓HSP70, ↓Ki-67, ↓telomerase | [216] |
| Naringin | Esophagus | In vitro (YM1 cancer stem cell) In vivo (YM1 xenograft mouse) |
In vitro (354 μM) In vivo (50 mg/kg) |
+Doxorubicin | — | Reduce side effect, restore the antioxidant defense system | ↑SOD | [217] | |
| AIF | Esophagus | In vitro (Eca109, KYSE-30 cells) In vivo (Eca109 xenograft nude mice) |
In vitro (5 μM) In vivo (20 mg/kg/day) |
+Radiation In vitro (6 Gy) In vivo (2 Gy/min on days 10 and 30) |
DCFH-DA confocal microscope | Synergistic effects: enhance apoptosis G2/M arrest | ↑ROS, ↓Nrf2, ↓HO-1, ↓NQO1, γ↑H2AX | [218] | |
| Wogonin | Larynx | In vitro (HN2, -HN3, -HN4, -HN5, and -HN9; SNU-1041, SNU-1066, and SNU-1076; HN4-cisR and HN9-cisR cells; normal cell: HOK-1, HOF, and HEK) In vivo (HN4-cisR or HN9-cisR xenograft nude mice) |
50 mg/kg | +Cisplatin | DCFH-DA flow cytometry | Synergistic effects: enhance apoptosis | ↑ROS, ↓GSH, ↓Nrf2, ↓GST, ↑p53, ↑p-JNK, ↑c-PARP, ↑PUMA | [219] | |
|
| |||||||||
| Polyphenols | Curcumin | Oral cavity | In vitro (normal cell SGNs and cancer cell PE/CA-PJ15) In vivo (male adult Wistar rats) |
In vitro (3.37, 6.75 μM) In vivo (200 mg/kg) |
+Cisplatin | — | Otoprotective effect: antioxidant activity Synergistic effects: prooxidant and anti-inflammatory |
Protective mechanisms: ↑Nrf2, ↑HO-1, ↓p53, ↓NF-κB Synergistic mechanisms: ↓Nrf2 (nuclear), ↓NF-κB, ↓pSTAT-3, ↑p53 |
[223] |
| Curcumin | Pharynx | In vitro (HPV-cells: FaDu, SQ20B, JHU-022, HEK-001, and MSK-Leuk1; HPV+ cells: UPCI-SCC090 and UPCI-SCC154) In vivo (FaDu xenograft nude mice) |
In vitro (10 μM) In vivo (10 μM) |
+Radiation In vitro (0, 2, 4, 6 Gy) In vivo (0, 2, 4, 6 Gy) |
— | Synergistic effects: inhibition of antioxidant defense system | ↓TxnRd1 | [145] | |
| FA | Oral cavity | In vitro (normal cell SGNs and cancer cell PE/CA-PJ15) In vivo (male adult Wistar rats) |
In vitro (100-600 μM) In vivo (600 mg/kg) |
+Cisplatin | — | Otoprotective effect: antioxidant activity Synergistic effects: prooxidant at lower concentrations (100-600 μM) Antagonistic effect: antioxidant at higher concentrations (>600 μM) |
Protective mechanisms: ↑Nrf2, ↑HO-1, ↓P53 Synergistic mechanisms: ↓Nrf2 (nuclear), ↓pSTAT-3 Antagonistic mechanisms: ↑Nrf2 (nuclear), ↑pSTAT-3 |
[223] | |
| DPP-23 | Larynx | In vitro (HN3, HN3-cisR, HN4, HN4-cisR, HN9, HN9-cisR, HOK-1 cells) In vivo (HN9-cisR xenograft nude mice) |
In vitro (2-40 μM) In vivo (10 mg/kg) |
+Cisplatin In vitro (10 μM) In vivo (5 mg/kg) |
DCFH-DA flow cytometry | Synergistic effects: inhibition of antioxidant defense system and activation of apoptosis | ↑ROS, ↓GSH, ↓Nrf2, ↓HO-1, ↑p53, ↑c-PARP, ↑p21 | [224] | |
| EGCG | Oral cavity | In vitro (normal cell: NHOK; cancer cell: HSC-2) |
50-100 μM | +Doxorubicin 0.625-5 μM | DCFH-DA fluorescence microscope | Chemoprotective effect | ↓ROS | [225] | |
| TA | Oral cavity | In vitro (normal cell: NHOK; cancer cell: HSC-2) |
12.5-50 μM | +Doxorubicin 0.625-5 μM | DCFH-DA fluorescence microscope | Chemoprotective effect | ↓ROS | [225] | |
| Epicatechin | Oral cavity | In vitro (oral fibroblast cells) In vivo (Zebrafish) |
In vitro (50 μM) In vivo (200 μM) |
+Radiation In vitro (20 Gy) In vivo (20 Gy) |
DCFH-DA flow cytometry | Radioprotective effect: reduce apoptosis and restore MMP | ↓ROS, ↓p38, ↓p-JNK, ↓CC3 | [226] | |
| Epicatechin | Oral cavity | In vitro (human keratinocyte HaCaT cell) In vivo (Sprague-Dawley rats) |
In vitro (100 μM) In vivo (2 mM/day after radiation for 23 days) |
+Radiation In vitro (20 Gy) In vivo (30 Gy) |
DCFH-DA flow cytometry | Radioprotective effect | ↓ROS, ↓p-JNK, ↓p38, ↓CC3, ↓NOX3 | [227] | |
|
| |||||||||
| Quinones | Plumbagin | Tongue | In vitro (CAL27 cell, cisplatin-resistant cell line CAL27/CDDP) In vivo (CAL27/CDDP xenograft nude mice) |
In vitro (5 μM) In vivo (3 mg/kg every two days) |
+Cisplatin In vitro (16.7 μM) In vivo (4 mg/kg every three days) |
DCFH-DA+MitoSOX fluorescence microscope | Synergistic effects: enhance apoptosis and autophagy | ↑ROS, ↓Bcl-2, ↑Bax, ↑CC3, ↑Beclin-1, ↓p62, ↑LC-II/LC-I, ↓p-AKT, ↓p-mTOR, ↑p-JNK | [238] |
| β-Lapachone | Head and neck | In vitro (FaDu, Detroit 562, SqCC/Y1, UMSCC-10A) In vivo (SqCC/Y1 xenograft SCID-NOD mice clinical samples) |
In vitro (2.5 μM) In vivo (10 mg/kg every other day) |
+Radiation In vitro (2 Gy) In vivo (10 Gy) |
DCFH-DA flow cytometry | Synergistic effects: enhance apoptosis and NDA damage | ↓NQO1, ↑ROS, ↓Bcl-2, ↓ATP, ↑γH2AX | [233] | |
|
| |||||||||
| Terpenoids | Oridonin | Larynx | In vitro (Hep-2 and Tu212 cells) In vivo (Hep-2 xenograft nude mice) |
In vitro (12, 24, and 36 μM) In vivo (20 mg/kg) |
+Cetuximab In vitro (10 μg/ml) In vivo (1 mg/mice) |
DCFH-DA flow cytometry | Synergistic effects: enhance apoptosis and G2/M arrest | ↑ROS, ↑CC8, ↑CC3, ↑c-PARP, ↑p21, ↑Fas, ↑FADD, ↑FasL, ↓ICAD, ↓cyclin B1, ↑p-cdc2, ↑p-cdc25c, ↓NAC, ↓CAT, ↑p-JNK, ↓p-EGFR | [244] |
|
| |||||||||
| Ginsenosides | Ro | Esophagus | In vitro (ECA-109, TE-1 cell) |
50 μM | +5-Fluorouracil 100 μg/ml | — | Synergistic effects: enhance DNA repair and inhibit autophagic flux | ↑ESR2, ↑NCF1, ↑ATG-7, ↑CC3, ↑CC9, ↑c-PARP, ↑p62, ↓LC3BII/LC3BI, ↑CHEK1 | [248] |
| KRG | Oral cavity | In vitro (normal keratinocyte HaLa cell, cancer SCC25, SCC1484 cell) In vivo (zebrafish) |
In vitro (10-100 μg/ml) In vivo (30 μg/ml) |
+Radiation In vitro (8 Gy) In vivo (20 Gy) |
DCFH-DA flow cytometry | Radioprotective effect | ↓ROS, ↓ATM, ↓p-p53, ↓p-JNK, ↓p-p38, ↓CC3 | [249] | |
Note. ROS: reactive oxygen species; DCFH-DA: 2′,7′-dichlorofluorescein diacetate; SOD: superoxide dismutase; AKT: protein kinase B; p-AKT: phosphorylated AKT; JNK: c-Jun N-terminal kinase; p-JNK: phosphorylated-JNK; c-FOS: cellular oncogene fos; Bcl-2: B-cell lymphoma-2; Bcl-xL: B-cell lymphoma-extra large; Bax: Bcl-2-associated X protein; NOS: nitric oxide synthase; HSP70: heat shock protein 70; AIF: alpinumisoflavone; Nrf2: nuclear factor (erythroid-derived 2)-like 2 transcription factor; HO-1: heme oxygenase; NQO1: NAD(P)H:quinone oxidoreductase 1; γH2AX: H2A histone family member X; GSH: glutathione; GST: glutathione-S-transferases; p53: protein 53; c-PARP: cleaved poly-ADP ribose polymerase; PUMA: p53 upregulated modulator of apoptosis; NF-κB: nuclear factor kappa-B; STAT: signal transducer and activator of transcription; TxnRd1: thioredoxin reductase 1; FA: ferulic acid; p21: protein 21; EGCG: epigallocatechin gallate; TA: tannic acid; CC3: cleaved caspase 3; NOX3: triphosphopyridine nucleotide oxidase 3; p62: sequestosome-1; LC3-II: light chain 3 II; LC3-I: light chain 3 I; p-mTOR: phosphorylated mammalian target of rapamycin; CC8: cleaved caspase 8; FADD: Fas-associated death domain; FasL: Fas ligand; ICAD: caspase-3-activated DNase inhibitor; p-cdc2: phosphorylated cdc2; p-cdc25c: phosphorylated cdc25c; NAC: N-acetyl cysteine; CAT: catalase; EGFR: epidermal growth factor receptor; p-EGFR: phosphorylated EGFR; Ro: ginsenoside Ro; ESR2: estrogen receptor 2; NCF1: neutrophil cytosolic factor 1; ATG-7: autophagy-related 7; CC9: cleaved caspase 9; CHEK1: checkpoint kinase 1; KRG: Korean red ginseng; p-p53: phosphorylated p53.