ROS-Mediated Therapeutic Strategy in Chemo-/Radiotherapy of Head and Neck Cancer

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.