Table 3.

In vivo paradigms of NOS chemo-inhibitors/NO donors for colon cancer treatment

Compound	In Vivo Model	Mechanism	Treatment (Dose/Duration)	Therapeutic Efficacy	Ref.
1400W	Genetically engineered xenograft mice model with constitutive iNOS expression (colon adenocarcinoma DLD-1)	Angiogenesis pathway	6 mg/kg-1/h-1 1400W/13 days	Inhibited tumor growth	[65]
Nobiletin (NOB)	AOM/DSS colon cancer model on CD-1 mice	iNOS ↓ antioxidative enzymes ↑ cell cycle ↓	AIN93G diet containing NOB (0.05 wt % in diet)/ 1 week after the AOM injection until the end of study	Suppressed colitis-associated colon carcinogenesis	[69]
All-Trans Retinoic Acid (AtRA)	Ex vivo; colonic mucosa of patients with CAC and UC	LPS/TLR4/NF-κB signaling pathway NOS2 ↓ TNF-α ↓	10–7 M AtRA/6 h; stimulated with 10 μg/mL lipopolysaccharide (LPS)	Clinically prevented the CAC development and progression	[70]
Fucoxanthin-Rich Brown Algae Extract (FX-BAE)	DSS-induced colitis and CACC model in BALB/c mice	Oxidative stress↓	Colitis: fed with FX-BAE 1, 2, or 5 g/kg/day from day 8 to day 14; CACC: fed with FX-BAE at 0.5, 1, or 2.5 g/kg every 2 days	Decreased the incidence of colonic neoplasm; increased superoxide dismutase (SOD) production, lymphocyte proliferation; prolonged survival rate in CACC mice	[71,72]
Polyphenol Ellagic Acid	1,2-dimethylhydrazine-induced colon cancer model on Wistar albino rats	Anti-inflammatory NF-κB pathway ↓ iNOS ↓ COX-2 ↓ TNF-α ↓ IL-6 ↓	60 mg/kg ellagic acid/p.o./every day for 15 weeks	Chemo-prevention on colon carcinogenesis	[75]
Cannabidiol (CBD)	Colo205 xenograft model on BALB/c nude mice	CBD overcomes NOS-induced oxaliplatin resistance by inducing autophagy	CBD + oxaliplatin (i.p.)	Overcame the resistance to oxaliplatin	[77]
Cetuximab	Ex vivo; CRC tissue explant culture	iNOS ↓ immunosuppressive cytokines ↑	Cetuximab + chemotherapy (CTX + Chemo)	Potentiated the chemo-therapeutic efficacy	[78]
NCX-4016	TNBS-AMO colon cancer model on rats	Independent of any inhibitory activity on COX-1 or COX-2	10 mg/kg NCX-4016 after four- weeks administration of AOM	Reduce aberrant crypt foci (ACF) in colon	[97]
NOSH–aspirin (NBS-1120)	Human colon cancer xenograft model	cell proliferation ↓ apoptosis ↑ the blockage of G(0)/G(1) cell cycle		Reduced the tumor volume by 85%	[98]