Table 2.
Old drugs modulating ROS as an adjuvant agent in the chemo-/radiotherapy of HNC.
| Drug | Site | Experimental model | Effective dose | Cotherapy | ROS detection | Biological effects | Mechanisms | Reference |
|---|---|---|---|---|---|---|---|---|
| Sulfasalazine | Larynx | In vitro (HN3, HN4, and HN9; HN3-cisR, HN4-cisR, and HN9-cisR cells) In vivo (HN9-cisR xenograft nude mice) |
In vitro (1 mM) In vivo (250 mg/kg daily) |
+Cisplatin In vitro (20 μM) In vivo (5 mg/kg weekly) |
DCFH-DA flow cytometry | Synergistic effect | ↑ROS, ↓GSH, ↓xCT, ↑γH2AX | [162] |
|
| ||||||||
| DCA | Larynx | In vitro (HN2, 3, 4, 5, 9, and 10; SNU-1041, 1066, and 1076; HN4-cisR and HN9-cisR cells) In vivo (HN4-cisR and HN9-cisR xenograft nude mice) |
In vitro (15-30 mM) In vivo (0.5 g/l once per week) |
+Cisplatin In vitro (10-30 μM) In vivo (5 mg/kg once per week) |
DCFH-DA+MitoSOX flow cytometry and confocal microscopy | Synergistic effect: enhances apoptosis | ↑mROS, ↓ΔΨm, ↓PDK2, ↑p21, ↓pPDHE1α, ↑c-PARP, ↑PUMA, ↑CC3 | [165] |
|
| ||||||||
| Melatonin | Oral cavity | In vitro (Cal-27, SCC-9 cell) |
1.5 mM | +Radiation (8 Gy) | DCFH-DA spectrofluorometer | Synergistic effects: enhance apoptosis and lethal autophagy | ↑GSSG/GSH, ↑Bax/Bcl-2, ↓NIX, ↑ATG12-ATG5 | [173] |
|
| ||||||||
| Melatonin | Oral cavity | In vitro (Cal-27, SCC-9 cell) |
1.5 mM | +Cisplatin (10 μM) | DCFH-DA spectrofluorometer | Synergistic effects: enhance apoptosis and lethal autophagy | ↑GSSG/GSH, ↑Bax/Bcl-2, ↑NIX, ↑ATG12-ATG5 | [173] |
|
| ||||||||
| Thioridazine | Larynx | In vitro (AMC-HN4 cell) |
10 μM | +Carboplatin | DCFH-DA+MitoSOX flow cytometry and fluorescence microscope | Synergistic effect: enhances apoptosis | ↑ROS, ↓PSMA5, ↑Nrf2, ↓c-FLIP, ↓Mcl-1, ↑c-PARP, ↑CC3 | [180] |
|
| ||||||||
| Aspirin | Larynx | In vitro (HN3, 4, and 9; HN3R, 4R, and 9R cells) In vivo (HN9R xenograft nude mice) |
In vitro (5-10 mM) In vivo (10 mg/kg daily) |
+Sorafenib In vitro (5-10 μM) In vivo (10 mg/kg daily) |
DCFH-DA flow cytometry | Synergistic effect | ↑ROS, ↓xCT, ↓GSH, ↑c-PARP, ↓p65, ↓Mcl-1 | [183] |
|
| ||||||||
| Aspirin | Larynx | In vitro (HN3, 4, and 9; HN3R, 4R, and 9R cells) In vivo (HN9R xenograft nude mice) |
In vitro (5-10 mM) In vivo (10 mg/kg daily) |
+Cisplatin In vitro (10 μM) In vivo (5 mg/kg weekly) |
DCFH-DA flow cytometry | Synergistic effect | ↓xCT, ↓GSH, ↑c-PARP, ↓p65, ↓Mcl-1, ↑p-p53 | [183] |
|
| ||||||||
| Salinomycin | Nasopharynx | In vitro (CNE-1, CNE-2, SUNE1, 6-10B, 5-8F, SUNE1R cell) |
2 μM | +Radiation (4 Gy) | DCFH-DA flow cytometry | Synergistic effect: enhances apoptosis | ↑ROS, ↓Nrf2, ↓survivin | [186] |
| Metformin | HNSCC | In vitro (HN30, HN31 cell) Clinical samples |
2.5 mM | +Radiation (4 Gy) | DCFH-DA flow cytometry | Synergistic effect: induces senescence | ↑ROS, ↓ME2, ↑p21, ↑NADP/NADPH, ↑SA-β-gal | [192] |
Note. mM: millimole; μM: micromole; DCFH-DA: 2′,7′-dichlorofluorescein diacetate; ROS: reactive oxygen species; GSH: glutathione; GSSG: oxidized glutathione; xCT: cysteine-glutamate antiporter; γH2AX: H2A histone family member X; DCA: dichloroacetic acid; mROS: mitochondrial reactive oxygen species; ΔΨm: mitochondrial membrane potential; PDK2: pyruvate dehydrogenase kinase 2; p21: protein 21; PDHE1α: pyruvate dehydrogenase E1-α; c-PARP: cleaved poly-ADP ribose polymerase; PUMA: p53 upregulated modulator of apoptosis; CC3: cleaved caspase 3; Bcl-2: B-cell lymphoma-2; Bax: Bcl-2-associated X protein; NIX: adenovirus E1B 19 kDa interacting protein 3-like; ATG: autophagy related; PSMA5: proteasome subunit alpha 5; Nrf2: nuclear factor E2-related factor 2; c-FLIP: cellular FLICE-like inhibitory protein; Mcl-1: myeloid cell leukaemia-1; p65: protein 65; p-p53: phosphorylated protein 53; ME2: malic enzyme 2; NADP: nicotinamide adenine dinucleotide phosphate; NADPH: nicotinamide adenine dinucleotide phosphate oxidase; SA-β-gal: senescence-associated β-galactosidase.