Table 1.

Proposed anti-cancer mechanisms and molecular targets of tetrahydrocurcumin.

	Targeted Cancer	Experimental Model	Tetrahydrocurcumin Concentration	Mechanism of Actions	References
Anti-oxidative activity
Radical scavenging	-	DPPH radical solution	IC50 = 4.1 ~ 20.7 μM	Radical scavenging	[32,59,60]
	-	PMA-induced cells	IC50 = 200 μM	O2-• Radical scavenging	[60]
	-	Hypoxanthine/xanthine oxidase reaction	300 μM	O2-• Radical scavenging	[59]
	-	Fe2SO4/H2O2 reaction	200 μM	OH• Radical scavenging	[59]
	-	SNAP reaction	IC50 = 104.2 μM	NO Radical scavenging	[59]
Reduction of oxidative damage	-	AAPH-induced linoleic oxidation	1–12 μM	Reduced lipid peroxidation	[32]
	Renal	Fe-NTA-induced renal damage in male ddY mice	0.5% in diet for 4 weeks	Reduced DNA, lipid, and protein oxidative damage	[28]
Induction of antioxidant	Renal	Fe-NTA-induced renal damage in male ddY mice	0.5% in diet for 4 weeks	Upregulated antioxidant enzymes	[28]
	Liver	As-induced hepatotoxicity in male albino Wistar rats	80 mg/kg for 4 weeks	Reduced lipid peroxidation Upregulated antioxidant enzymes	[61]
	Liver	Cd-induced hepatotoxicity in male albino Wistar rats	20, 40, and 80 mg/kg for 4 weeks	Reduced lipid peroxidation Upregulated antioxidant enzymes	[62]
Modulation of Phase I and Phase II enzymes	-	Murine hepatoma cells Hepa 1c1c7	-	Upregulated NAD(P)H: quinone oxidoreductase	[63]
	-	Human CYP450 enzymes	0.01–100 μM	Inhibited CYP2C9 and CYP3A4 activity	[36]
	-	Acetaminophen-induced liver injury in male Kunming mice	25, 50, and 100 mg/kg	Downregulated CYP2E1 gene Downregulated Kepa1 Upregulated Nrf2 and downstream genes	[64]
Anti-inflammatory activity	-	TPA-stimulated HL-60 cells and mouse skin	in vivo study: 810 nmol	Decreased ROS production Decreased MPO activity	[65]
	-	LPS-treated RAW264.7 macrophage and C57BL/6 mice	in vitro study: 10 and 50 μM in vivo study: 100 mg/kg	Decreased TNF-α production Downregulated phospho-IκB and NF-κB	[66]
	-	LPS-treated RAW264.7 macrophage	3.125–100 μM	Decreased NO, TNF-α, IL-6 production Downregulated NF-κB nuclear translocation	[67]
	Colon cancer	DSS-induced colitis in ICR mice	0.1 and 0.25 mmol/kg for 7 days	Downregulated NF-κB and STAT3 DNA binding activity Downregulated iNOS and COX-2	[68]
	-	Soybean lipooxygenase	1, 10, and 250 μg/mL	Downregulated lipoxygenase activity	[36]
	-	Molecular docking assay	-	Possible phospholipase A2 inhibitor	[52]
Anti-proliferative activity	-	TPA-stimulated mouse skin and JB6 cells	in vitro study: 5 and 10 μM in vivo study: 1 and 3 μmol	Reduced ODC activity Decreased anchorage-independent growth	[69]
	Colon cancer	DMH-initiated mice	Dietary 0.5% for 7 weeks	Reduced ACF formation and crypt proliferation	[70]
	Colon cancer	AOM-treated mice	Dietary 0.005 and 0.02% for 23 weeks	Reduced ACF formation Downregulated iNOS and COX-2 Decreased PCNA Downregulated Wnt-1/β-catenin/p-GSK3β signaling	[71]
	Glioma	Glioma cells (alone or combined with radiation)	3–161 μM	Reduced colony formation Induced G0/G1 cell cycle arrest Downregulated cyclin D1 and PCNA Increased GSH depletion	[72]
Anti-metastatic activity	Fibrosarcoma	HT1080 human fibrosarcoma cells	5–100 μM	Decreased invasion and migration Decreased cell adhesion Downregulated MMPs and uPA	[73]
	Liver cancer	HepG2 xenograft model	Oral 3000 mg/kg for 21 days	Decreased angiogenesis	[46]
	Cervical cancer	CaSki xenograft model	Oral 100, 300 and 500 mg/kg for 30 days	Decreased angiogenesis Decreased tumor volume Downregulated HIF-1α, VEGF, VEGFR2, EGFR, COX-2 Downregulated p-ERK1/2 and p-AKT	[74,75]
	Osteosarcoma	Lung metastasis model Osteosarcoma cell lines	in vitro study: 2.5–50 μM in vivo study: i.p. 100 mg/kg for 8 days	Reduced lung metastasis Decreased invasion and migration Promoted MET process Downregulated HIF-1α, VEGF, and MMPs Decreased hypoxia-induced angiogenesis	[76]
Induction of programmed cell death	Breast cancer	MCF-7 cells	15–130 μM	Induced mitochondria-dependent apoptosis Loss of ΔΨm Increased ROS production Upregulated Bax and Downregulated Bcl-2 Upregulated p21 Activation of caspases	[77,78]
	Liver cancer	H22 ascites tumor-bearing mouse model	i.p. 5, 10 and 20 mg/kg for 7 days	Induced mitochondria-dependent apoptosis Upregulated Bax and Downregulated Bcl-2 Activation of caspases Upregulated p53 and downregulated MDM2	[79]
	Leukemia	HL-60 cells	25–100 μM	Induced autophagy Upregulated LC3 I/II and beclin-1 Downregulated PI3K/Akt and mTOR/p70S6K signaling	[80]
	Leukemia	Cytarabine-resistance HL-60 cells	5–100 μM	Induced autophagy Upregulated p62 and beclin-1	[81]
	Lung cancer	A549 cells	30–130 μM	Induced autophagy Upregulated LC3 I/II and beclin-1 Downregulated PI3K/Akt/mTOR signaling	[82]
Immuno-modulating activity	-	RAW264.7 macrophages and LPS-stimulated mouse splenocytes	1–10 μg/mL	Increased phagocytosis Increased NK cells activity	[83,84]

AAPH, 2′-azobis(2-amidinopropane)hydrochloride; ACF, aberrant crypt foci; Akt, protein kinase B; AOM, azoxymethane; Bax, Bcl-2-associated X Protein; Bcl-2, B cell lymphoma 2; COX-2, cyclooxygenase 2; CYP, cytochrome P450 enzyme; DMH, 1,2-dimethylhydrazine; DPPH, 2,2-diphenyl-1-picrylhydrazyl; DSS, dextran sodium sulphate; EGFR, epidermal growth factor receptor; Fe₂SO₄, ferric sulfate; Fe-NTA, ferric nitrilotriacetate; GSH, glutathione; H₂O₂, hydrogen peroxide; HIF-1α, hypoxia-inducible factor 1α; IL-6, interleukin-6; iNOS, onducible nitric oxide synthase; IκB, inhibitor of kappa B; LC3 I/II, Protein light chain 3 I/II; LPS, lipopolysaccharide; MDM2, murine double minute 2; MET, mesenchymal epithelial transition; MMPs, matrix metalloproteinases; MPO, myeloperoxidase; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; NF-κB, nuclear factor kappa B; NO, nitric oxide; Nrf2, nuclear factor erythroid 2-related factor 2; O₂^-•, superoxide anion radical; ODC, ornithine decarboxylase; OH•, hydroxyl radicals; p70S6K, 70-kDa ribosomal S6 kinase; p-AKT, phosphorylated protein kinase B; PCNA, proliferation cell nuclear antigen; p-ERK1/2, phosphorylated extracellular signal-regulated kinases1/2; p-GSK3β, phosphorylated glycogen synthase kinase 3β; PI3K, phosphatidylinositol-3-kinase; PMA, phorbol 12-myristate 13-acetate; ROS, reactive oxygen species; SNAP, S-nitroso-N-acetylpenicillamine; STAT3, signal transducer and activator of transcription -3; TNF-α, tumor necrosis factor α; TPA, tetradecanoylphorbol-13-acetate; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; Wnt-1, Wnt family member 1; ΔΨm, mitochondrial transmembrane potential.