Table 1.

Key neem components and their potential targets.

S.N.	Components	Functions	Target	Model system	Ref
1.	Neem leaf extract (NLE)	Proliferation-inhibitory effect	Multiple cell cycle molecules	Prostate cancer cells	[18,19]
		Induces apoptosis	Multiple apoptosis-modulating molecules	Prostate cancer cells, primary chronic lymphocytic leukemia cells	[19,30]
		In vivo: proliferation inhibition	Proliferating cell nuclear antigen (PCNA) and cytokeratin	DMBA-induced HBP mouse model	[10,29]
		In vivo: apoptosis induction	Bim, Bax, Apaf-1, caspases, and Bcl-2	Breast cancer tissue, prostate cancer xenografts, and DMBA-induced HBP oral carcinogenesis model	[10,18,29,45–47]
		Enhances immunity	Peripheral blood mononuclear cells (PBMCs), macrophages, natural killer (NK) cells, CD40–CD40L, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α)	Murine Ehrlich carcinoma and B16 melanoma	[50,51]
		Enhances immunity	Spleen and peripheral blood: macrophages, cytokines, and immune cells	Ehrlich’s carcinoma cells, B16 melanoma, lung sarcoma and lymphosarcoma in the liver in Balb/c mouse model.	[49,52–54]
		Increases the immunogenicity of vaccinations	Surface antigen of B16 melanoma cell (B16MelSAg), breast tumor associated antigen (BTAA), and carcinoembryonic antigen (CEA)	B16 melanoma tumor, breast cancer cells, and CEA + colorectal cancer cells	[53,55,56]
		Alleviates mutagenicity of carcinogens	Likely drug metabolizing enzymes	In vivo bone marrow micronuclei test	[55,68,71]
		Maintain cellular redox balance	Antioxidant phase II enzymes, glutathione level, protein oxidation, and lipid oxidation and peroxidation	Benzo(a)pyrene-induced stomach tumor model and DMBA-induced skin papilloma model, DMBA-induced rat mammary carcinogenesis model, MNNG-induced carcinogenesis model, and DMBA-induced HBP oral carcinogenesis model	[72–76,85,87]
		Attenuates angiogenesis	Human umbilical vein endothelial cells (HUVECs), vascular endothelial growth factor (VEGF)	DMBA-induced HBP carcinogenesis model, chemical carcinogen-induced mammary tumorigenesis	[13,73,89]
2.	Azadirachtin	Induces apoptosis	Bcl-2 family proteins, survivin and caspase-3, -8, and -9	Cervical cancer cells	[23]
		Cell cycle arrest	p53, p21, cyclin B, cyclin D1, and PCNA	Human cervical cancer (HeLa) cells	[23]
3.	Nimbolide	Cell cycle arrest	Cyclins, CDKs, and CKIs, cell cycle checkpoint proteins are CHK2 and Rad17	Colon carcinoma cells	[24,25]
		Induces apoptosis	Bcl-2 family proteins, survivin, and caspase-3, -8, and -9.	Breast, prostate, hepatocarcinoma, cervical, choriocarcinoma, colon, lymphoma, leukemia, and melanoma	[20,23,26,27]
		Disrupts cell cycle progression	Unclear	Breast, cervical, choriocarcinoma, lymphoma, leukemia cells HL-60, THP1, and melanoma cells	[20,23,26,27]
		Retards tumor cell migration, invasion, and angiogenesis	Metalloproteinase-2/9 (MMP-2/9), VEGF, ERK1/2, NF-κB	Colon cancer cells	[25]
		Inhibits cell growth	Unclear	Breast cancer cells	[20]
4.	Gedunin	Inhibits cell proliferation	Bioinformatic analysis identifies 52 genes involved	Ovarian cancer cells	[28]
5.	Neem leaf glycoprotein (NLGP)	Increases host immunity	Various immune cells in favor for type 1 immunity, maturation of dendritic cells	PBMC derived from HNSCC patients, myeloid derived dendritic cells	[57–61]
		Relieves tumor immune suppression	Regulatory T cells (Tregs)	Mouse tumor model	[64]
		Restores the impaired chemotactic activity of PBMC	CXCR3-mediated axis, CCR5-mediated axis, CXCR4-mediated axis	PBMC derived from HNSCC patients	[66]
		Maturation of DCs and increased immunity against CEA	Maturation of dendritic cells, various immune cells	Swiss mice, peripheral blood from HNSCC patients	[58,59,67–69]
6.	Mixture of neem limonoids and other components	Induces apoptosis	Intrinsic: cytochrome c, Bcl-2 family proteins Extrinsic: death receptors	Leukemia, prostate, cervical, colon, stomach, breast, choriocarcinoma, and hepatocarcinoma	[14,16,18,20,23,30–32,102]
		Induces caspase-independent cell death	Apoptosis-inducing factor (AIF)	Prostate	[32]
		Induces autophagy	Unclear	Prostate and colon	[32]
		Alleviates mutagenicity of carcinogens	Likely drug metabolizing enzymes	In vitro Ames test	[71]
		Maintain cellular redox balance	Phase I reactions and phase II enzyme GST	Rat	[84,86]