Table 1.

Targeting KP enzymes in preclinical studies on antineoplastic therapy.

Tumor	Target	Mechanism of Action and Agent	Suppression of Tumor Growth	Comments	References
Colon cancer	IDO1	Direct enzyme inhibition		In-vitro SW837 cell line culture In-vivo Balb/c mice bearing CT26 tumor	[64,96,97,98,99,100,101,102]
		1-MT	7%
		4,6-substituted-1H-indazole derivatives	38%
		Amidoxime	N/A
		Epacadostat	56%
		epigallocatechin gallate, Navoximod	N/A 75% (in co-treatment with oxaliplatin)
		4-Bromophenylhydrazinyl benzenesulfonylphenylureas	25%
Ehrlich ascites carcinoma	IDO1	Direct enzyme inhibition		In-vivo ICR mice bearing Erlich tumor	[97]
		Ethyl pyruvate	78% (in co-treatment with cyclophosphamide); 79% (in co-treatment with cycloplatam)
		Amidoxime	88% (in co-treatment with cyclophosphamid); 85% (in co-treatment with cycloplatam)
Gastrointestinal stromal tumors	IDO1	Downregulation of oncogenic KIT tyrosine-protein kinase signaling		In-vivo C57Bl/6J mice bearing GIST-T1 tumor	[103]
		Imatinib	70%
Glioblastoma	IDO1	Direct enzyme inhibition		In-vivo C57BL/6 mice bearing GL261 glioblastoma	[83,104,105,106,107]
		1-MT	63% (in conjunction with two-fraction radiotherapy)
		Dinaciclib	N/A
		Acyclovir	N/A
Glioma	IDO1	Direct enzyme inhibition		In-vitro A172 human glioma cell line culture In-vivo C57BL/6 mice bearing LN229 glioma	[107,108,109]
		1-MT	87% (in co-treatment with temozonlomide)
		Tryptamine	N/A
		N-dimethyltryptamine	64% (in combiantion with carboxyamidotriazole and cytotoxic T lymphocytes therapy)
HPV-associated tumors	IDO1	Direct enzyme inhibition		In-vivo 57BL/6 mice bearing TC-1 tumor	[93]
		1-MT	60% (in combiantion with gDE7-based immunotherapy)
Lung cancer	IDO1	Direct enzyme inhibition		In-vitro NCI-H460 and A549 cell line cultures In-vivo C57BL6/N mice bearing LLC, LL24 tumor lines, Balb/c nude mice bearing NCI-H1299 tumor	[94,95,110,111,112,113,114,115,116]
		1-MT	47%
		Navoximod	65%
		EOS200271	45%
		LW106	68%
		Epacadostat	51%
		INCB023843	22%
		Downregualtion of enzyme expression
		Feiji Recipe	60%
		Inhibition of the extracellular IDO1 secretion
		Stragaloside IV	N/A
		Astragaloside IV	72% (in combination with anti-PD1 antibody)
Thymona		Downregualtion of enzyme expression		In-vivo C57BL/6 mice bearnng EG7 tumor line	[117]
		Resveratrol	51%
Melanoma	IDO1	Direct enzyme inhibition		In-vitro 624.38mel cell line culture In-vivo BALB/c mice bearing B16F10 melanoma	[94,95,113,118,119,120,121,122,123]
		1-MT	52% (in co-treatment with cyclophosphamide) 48% (in co-treatment with pimozide) 46% (in monotherapy),
		Navoximod	95% (in co-treatment with pmel-1 T cells and gp100 peptide vaccination)
		Epacadostat	50%
		DX-03-12	72.2%
		LW106	65%
		NTRC 3883-0	20%
		Increased proteasomal degradation
		Fludarabine	N/A
Myelodysplastic syndrome	IDO1	Direct enzyme inhibition		In-vivo C57BL/6N mice bearing MDS92 tumor	[124,125]
		Epacadostat	50%
Nasolaryngeal carcinoma	IDO1	STAT1 acetylation		In-vitro CNE2 and CNE1 cell line cultures In-vivo BALB/C (NU/NU) mice bearing C666-1 tumor	[126,127,128]
		Bortezomib	23%
		Suberoylanilide hydroxamic acid	41%
		Combination of bortezomib with suberoylanilide hydroxamic acid	76%
		Sodium butyrate	N/A
Ovarian cancer	IDO1	Direct enzyme inhibition		In-vitro SKOV3 cell line, patient-derived ovarian cancer cell culture In-vivo Balb/c NU/NU mice bearing SKOV3 tumor	[46,94,95,129,130]
		1-MT	10%
		NTRC 3883-0	N/A
		LW106	N/A
		BMS-986242	N/A
Pancreatic Ductal Adenocarcinoma	IDO1	Direct enzyme inhibition		In-vitro Human PDAC specimens	[124,131,132,133]
		Epacadostat	55%
		EOS200271	32%
Plasmacytoid dendritic cell leukemia	IDO1	Direct enzyme inhibition		In-vitro PMDC05 cell line culture	[134]
		Toho-1	N/A
Renal Cancer	IDO1	Direct enzyme inhibition		In-vivo Balb/cJ mice bearing 786-O tumor	[135]
		Methyl-thiohydantoin-DL-TRP	45% (in co-treatment with IFN-α)
Sarcomas	IDO1	Direct enzyme inhibition		In-vivo C57BL/6N mice bearing MCA205 tumor	[136]
		Navoximod	0% (did not show antitumoral activity, but has a potential impact on the NK cell functions).
Non-Hodgkin Lymphoma	IDO2	Direct enzyme inhibition Indoximod	77% (in co-treatment with cyclophosphamide)	In-vivo BalB/c NU/NU mice bearing A20 B-cell lymphoma	[137]
Breast cancer	IDO 1	Direct enzyme inhibition		In-vitro MDA-231and BT549 cell lines In-vivo C57BL/6 mice bearing MDA-231 tumor	[71,123,131,138,139]
		EOS200271	21%
		Downregulation of enzyme expression
		Nimesulide	54%
		Celecoxib	52%
		Increased proteasomal degradation
		Fludarabine	N/A
	TDO2	Direct enzyme inhibition
		680C91	85%
Cervical cancer	IDO1	Direct enzyme inhibition		In-vitro HeLa cell line	[140,141]
		LBJ-10	N/A
	IDO1 and TDO	Direct enzyme inhibition
		β-lapachone	N/A
Liver cancer	IDO1	Direct enzyme inhibition		In-vitro HepG2 cell line In-vivo BALB/c mice bearing H22 tumor C3HA mice bearing H-29 tumor	[142,143,144]
		Ethyl pyruvate	39%
		JAK/STAT1 pathway inhibition
		Polysaccharide from Lepista sordid	N/A
	TDO	Direct enzyme inhibition
		3-(2-(Pyridyl)ethenyl) indole derivatives	65% (in combination with irinotecan)
Multiple Myeloma	KMO	Direct enzyme inhibition		In-vitro Patient-derived multiple myeloma cell culture	[145]
		Ro-61–8048	N/A

IFN-α—interferon-α, N/A—Data not available.