Table 3.

Preclinical evidence targeting H4R for the treatment of melanoma, breast, lung, and testicular cancers.

Cancer type	Experimental model/cells	Outcome	References
Lung Cancer	Human NSCLC cell lines and xenograft NSCLC tumors	H4R agonist (4-methylhistamine): ↓tumor volume, ↑ survival, ↑ E-cadherin and ↓ vimentin (↓ EMT progress).	Cai et al., 2014
Breast cancer	Human MDA-MB-231 and MCF-7 cell lines	H4R agonists (histamine, clobenpropit, VUF8430): ↓ proliferation; ↑ apoptosis; ↑ senescence; cell cycle arrest.	Martinel Lamas et al., 2013; Medina et al., 2008, 2011
	MDA-MB-231 xenograft in mouse	H4R agonists (histamine, JNJ28610244): ↓ tumor volume; ↓ angiogenesis. Histamine: ↑ survival.	Martinel Lamas et al., 2013, 2015a
Melanoma	Human WM35 and M1/15 cell lines	H4R agonists (Clozapine, VUF8430): ↓ proliferation, ↑ senescence, inhibited forskolin-induced cAMP levels in M1/15, increased phosphorylation levels of ERK1/2 in both cell types.	Massari et al., 2013
	Human 1205Lu cell line	H4R agonists (histamine, Clozapine, JNJ28610244): ↓ proliferation, ↑ senescence, ↑ melanogenesis.	Massari et al., 2017
	M1/15 xenograft in mouse	Histamine and clozapine: ↓ tumor volume, ↑ survival.	Massari et al., 2013
	1205Lu xenograft in mouse	H4R agonists (histamine, Clozapine, JNJ28610244): ↓ tumor growth, ↓ mitotic index, and PCNA in tumor, ↓ metastatic spread, and angiogenesis.	Massari et al., 2017
Testicular cancer	Mouse MA-10 cell line	H4R agonists (JNJ28610244 and VUF8430): ↓ proliferation, VUF8430: ↓ LH/hCG-stimulated cAMP production and ↓progesterone production.	Abiuso et al., 2014
	Rat R2C cell line	H4R agonist (VUF8430): ↓ proliferation, ↓ steroidogenesis, ↓ pro-angiogenic capacity.	Abiuso et al., 2018

EMT, epithelial to mesenchymal transition; LH/hCG, luteinizing hormone/choriogonadotropin receptor; NK, natural killer; NSCLC, non-small cell lung cancer; OTSCC, oral tongue squamous cell carcinoma; PCNA, proliferating cell nuclear antigen.