Health functionality of apigenin: A review

Figures & data

Figure 1. Basic structure of flavonoids.^[6]

Figure 2. Structure of Apigenin.

Figure 3. Apigenin derivatives and natural analogues.^[29]

Figure 4. Structure of bi-apigenin.^[34]

Figure 5. Biosynthesis of apigenin and its derivatives.

Figure 6. Apigenin conjugates in plants.^{[30,33,41,42,45,47,48]}

Figure 7. A generalized model of apigenin absorption and distribution in humans and other mammalian models.^[82]

Figure 8. Phamacological properties of apigenin.

Figure 9. Possible role of apigenin in inducing anti-inflammatory affect by modulating the expression of cytokines and other inflammatory molecules at both transcriptional and post transcriptional level. COX 1/2 (Cycloxygenase 1/2), LOX (Lipoxygenase), HO-1 (Haeme oxygenase 1), PLA (Prostaglandins), IL (Interleukins), TNF-α (Tumor necrotic factor alpha), iNOS (inhibitor of nitric oxide synthase), INF-γ (Interferon gamma), XIAP (X-linked inhibitor of apoptosis protein), c-FLIP (Cellular FLICE like inhibitory protein). Lines with arrow heads represent activation while lines without arrow heads represent inhibition.

Table 1. Effect of apigenin on the regulation of various inflammatory molecules.

Experimental models and cell lines	Modulatory effect on oxidative stress markers	References
Human volunteers fed on parsley	↑GR and ↑SOD	[85]
Albino rats (in vivo)	↓LDH, ↓AST, ↓ALP, ↓ALT and ↓LPO, ↓PCC	[93]
IPEC-J2 cells	↓IL-6, ↓IL-8, ↓COX-2, ↓H2O2	[96]
Rats (contusive spinal cord injury) (in vivo)	↑SOD, ↑GSH-Px, ↓MDA, ↓IL-1β, ↓TNF-α, ↓ICAM	[121]
Rats (Lung schemia Reperfusion Injury)	↓IL-6, ↓IL-10, ↓TNF-α, ↓iNOS	[122]
RAW 246.7 Mouse macrophages	↓COX-2, ↓iNOS	[133]
HL-60 cells (in vitro)	↓XO	[139]
HCEC cervical cancer cell line	↓COX-2	[145]
Mice in vivo and in vitro (keratinocyte cell lines)	↓COX-2	[146, 147, 148]
Mice (in vitro)	↑GSH, ↑GST, ↑SOD, ↓MPO, ↓MDA, ↓AST, ↓ALT, ↓LDH, ↓Creatine and ↓BUN	[149]
Male mice (in vivo)	↑GSH, ↑GSH-Px, ↑SOD, ↓ALT, ↓AST, ↓COX-2, ↓iNOS and ↓TNF-α	[150]
Mice (in vivo)	↑GSH, ↑GST, ↑QR	[151]
LPS and human THP-1-induced macrophages and mouse J774A cells	↓IL-6, ↓IL-1β, ↓TNF-α	[152]
In vitro and in vivo rat hepatocytes	↑GSH, ↑GST, ↑SOD, ↑GSH-Px, ↑GSH-R, ↑CAT	[153]
Hep G2 cells	↓ NO, ↓ iNOS, and ↓ cPLA2	[154]
Copper induced AD cell model (in vitro)	↑ GSH, ↑SOD, ↑GSH-Px	[155]
LPS induced RAW 264.7 cells	↓COX-2, ↓iNOS, ↓NO	[156]
Wistar rats (in vivo)	↓LPO	[157]
Human PBMC (in vitro)	↓IL-6, ↓IL-1β, ↓TNF-α	[158]
Murine macrophage cells and mice (in vivo)	↓IL-6, ↓IL-1β, ↓TNF-α	[159]

NO: nitric oxide, iNOS: nitric oxide synthase, MDA: malondialdehyde, COX: cyclooxygenase, TNF: tumor necrotic factor, ICAM: intracellular adhesion molecules, LOX: lipooxygenase, GST: glutathione-S-transferase, LPO: lipid peroxidation, cPLA2: cytosolic phospholipase A2, GPx: glutathione peroxidise, GR: glutathione reductase.

Figure 10. Antioxidant enzyme targets of apigenin at both transcriptional and post transcriptional level. AST (Aspartate aminotransferase), ALT (Alanine aminotransferase), ALP (Alkaline phosphatase), LDH (Lactate dehydrogenase) GSH (Glutathione), GST (Glutathione S transferase), GPx (Glutathione peroxidase), GR (Glutathione reductase), P.Red (Peroxireductase), CAT (Catalase), SOD (Superoxide dismutase, 4-HNE (4 hydroxy 2 nonenal), LPO (Lipid peroxidation), GCL (Glutamylcysteine ligase), GS (Glutathione synthase), TF (Transcriptional factors). Lines with arrow heads represent activation while lines without arrow heads represent inhibition.

Table 2. Protective effect of apigenin against some of the numerous toxic compounds. Carbon tetrachloride (CCl₄), N-nitrosodiethylamine (NDEA), trinitrobenzene-sulfonic acid (TNBS), dextran sulphte sodium (DSS).

Toxicant	Dose of toxicant (T)/Dose of Apigenin or its derivative (A)	Experimental models and cell lines	Target organ/cell line	References
Acetaminophen	T- 350 mg/Kg b.w A- 100 & 200 mg/Kg b.w for 7 days	Mice	Liver	[164]
Copper	NA	AD cell lines	neuronal cell	[155]
Cisplatin	A- 5, 10, 20 mg/Kg b.w For 1 hr T- 40 µmol/L for varying durations	HK-2 cell line	human renal proximal tubular epithelial cells	[160]
Furan	NA	Mice	Liver and kidney	[149]
Cyclosporine	T- NA A- 10, 15, 20 mg/Kg b.w	Rats	Kidney	[165]
CCl4	NA	Male mice	Liver	[150]
CCl4 (in vivo/ in vitro)	T- 86 µmol/L (in vitro) A- 60- 0.006 µg/ml T- 1.25 ml/Kg b.w A- 80 mg/Kg b.w	Rats	Liver	[153]
Benzo(a)pyrene	T- 125 mg/Kg b.w A- 2.5 – 5 mg/Kg b.w	Mice	Liver	[166]
NDEA	T- 0.1 mg/ml in drinking water A- 10, 20, 40 mg/ml For 21 days	Rats	Liver	[93]
TNBS and DSS	T- NA A- 1, 3, 10 mg/Kg b.w	Rats	Intestine (colitis)	[163]
Alloxan induced diabetic rats	A- 0.78 mg/Kg b.w For 10 days	Rats	Liver, Thyroid, Pancreas	[167]
Arsenic, nickel chromium and cadmium	A- 100ng/ml (in vitro) and 0- 40 mg/Kg b.w for 5 days/3weeks (in vivo)	Beas-2B cells	Transformed human bronchial epithelial cells (CXCR4)	[168]
Ethinylestradiol	T- 0.5, 1.0 ml/ml A- 0.1, 0.5, 1.0 ml/ml	Transgenic Drosophila melanogaster (hsp70-lacZ)Bg9	Drosophila larva	[169]
DMBA painting in buccal pouch	A- 2.5 mg/ml	Golden Syrian hamster	Plasma and Buccal epithelial cells	[170]

Trinitrobenzenesulfonic acid (TNBS) model and the Dextran sulphate sodium (DSS) induced colitis model, 7,12-dimethyldenz(a) anthracene (DMBA). NA: not available, T: toxicant/s, A: apigenin and its derivatives.

Table 3. Antigenotoxic potential of apigenin on various cell lines and animal models against different genotoxic agents.

Test compound	Animal models and cell lines	Parameters used	References
Ethyl methane sulphonate (EMS), acridine, sodium azide and 9- amino acridine	EMS and acridine was used in Saccharomyces cerevisiae and sodium azide and 9- amino acridine was used in Salmonella typhimurium	Ames test	[56]
Doxorubicin	Mice bone marrow cells, polychromatic erythrocytes, blood lymphocytes, hepatocytes, kidney cells	Micronucleus test and comet assay	[57]
NDEA	Rat liver, lymphocyte and bone marrow cells	Micronucleus test (MNT) and comet assay	[93]
Benzo (a) pyrene	Mice	DNA strand breaks	[166]
Mitomycin c	Mouse bone marrow cells	Sister chromatid exchanges and chromosomal aberrations	[171]
Mitomycin c and cyclo-phosphamide	NA	Chromosomal aberrations, sister chromatid exchanges and cell cycle kinetics	[172]
Cyclophosphamide and doxorubicin	Bacterial culture in vitro and mice blood cells in vivo	Micronucleus test	[175]
UV-B and benzo (a) pyrene induced	Mice skin cancer	Cytogenetic determination of chromosomal aberrations (CA)	[176]
1-nitropyrene or 1,6-dinitropyrene	CHO cells	cytotoxicity and sister chromatid exchanges (SCEs)	[177]
Gamma Radiations	Human blood lymphocytes	Cytokinesis block micronucleus (CBMN) assay	[178]
Apigenin (in Matricaria chamomilla extract)	Drosophila wing	Drosophila wing spot test	[179]
Ethinylestradiol	Human blood lymphocytes	Chromosomal aberrations, sister chromatid exchanges and cell cycle kinetics	[180]
Hydrogen peroxide	Drosophila melanogaster	Somatic mutation and recombination test or wing spot test	[181]
Hydrogen peroxide	Human blood lymphocytes	Sister chromatid exchanges and cytokinesis blocked micronucleus assay	[182]
Radiation and mitomycin c	Human blood lymphocytes	Sister chromatid exchanges and cytochalacin blocked micronucleus assay	[183]
Gamma radiations	Human blood lymphocytes	Cytokinesis blocked micronucleus assay, nucleoplasmic bridges, nuclear buds and comet assay	[184]
UV-rays, Lomifloxacin, 4-nitroquinolineN-oxide	Episkin (a reconstructed skin model)	Comet assay	[185]
Crude latex obtained from Jatropha gossypifolia	Eryrthrocytes of a fresh water fish Channa punctatus	Micronucleus test and comet assay	[186]
S. typhimurium strain (TA1538 uvrB^− and TA1978 uvrB^−) and E. coli K12 strain PQ37	_	Ames test	[187]

Table 4. Apigenin as pro-oxidant, genotoxicant, or as an inhibitor of key enzymes to produce clastogenic effect in cancer cell lines.

Test compound	Animal models and cell lines	Parameters used	References
Apigenin	Human blood lymphocytes	Cytochalasin B blocked micronucleus assay	[173]
Apigenin	HepG2 cells	Sister chromatid exchange and chromosomal aberrations	[174]

Table 5. Protective role of apigenin among various cancer cell lines and in experimental animal models.

S. No	Types	Experimental models and cell lines	Conclusions	References
1.	Prostate cancer	virally transformed human (PZ HPV-7) and human prostate adeno carcinoma (CA HPV-10) cells.	Apigenin treatment resulted in significant apoptosis of human prostate adeno carcinoma (CAHPV- 10) cells, but not of virally transformed human prostate epithelial (PZ-HPV-7) cells. Apigenin at 1–10 mM concentration also resulted in a dose-dependent G2-M phase cell cycle arrest of CA-HPV-10 cells but not of PZ-HPV-7 cells.	[86]
		PC-3 cells	Apigenin inhibits Akt kinase activity by dephosphorylating it, which was confirmed by reduced phosphorylation of pro-apoptotic proteins BAD and glycogen synthase kinase-3.	[89,212]
		PC-3M cells	Apigenin markedly decreased HIF-1α and VEGF expression under both normoxic and hypoxic conditions in PC-3M cells time dependently. In recent studies it was observed that apigenin inhibited the focal adhesion kinase (FAK)/Src, motility and invasion in the metastatic prostate carcinoma.	[213, 214]
		PWR-1E, LNCaP, PC-3 & DU-145 cells	Apigenin drives the production of reactive oxygen species and initiates a mitochondrial mediated cell death pathway in several lines of prostate cancer epithelial cells by inhibiting PI3K/Akt signalling.	[215]
		PC-3 cells	Apoptosis was achieved in PC-3 cell lines by suppressing the expression of NF-κB-regulated genes, specifically, Bcl2, cyclin D1, cyclooxygenase-2, matrix metalloproteinase 9, nitric oxide synthase-2, and VEGF	[216]
		22RV1tumor, xenograft in athymic nude mice	Induces cell cycle arrest and apoptosis by down-regulating the protein expression of cyclin D1, D2, and E, cdk2, cdk4, and cdk6, decrease in Rb phosphorylation and increased accumulation of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18 protein in prostate cancer cell xenograft in athymic nude mice. Later studies demonstrated that apigenin at different doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome-c, p53 activation and apoptosis in human prostate cancer 22Rv1 cells.	[217, 218, 219]
		PC-3 cells, DU-145 cells and PC-3 Xenograft in athymic nude mice	Apigenin resulted in a dose dependent suppression of apoptosis suppressor proteins XIAP, cIAP1, cIAP2 and survivin. This is accompanied by decrease in BclxL and Bcl2 and an increase in Bax. An increase in Bax is due to the inhibition of Class II histone deacetylase protein which results in its dissociation from Ku 70, followed by apoptotic progression in both the cell lines and athymic nude mouse xenograft model.	[220]
		LNCaP and PC-3 cells	Apigenin causes G0/G1 phase arrest, decrease in total Rb protein and its phosphorylation at Ser780 and Ser807/811 in dose- and time-dependent fashion. Apigenin treatment also results in increased phosphorylation of ERK1/2 and JNK1/2 which resulted in decreased ELK-1 phosphorylation and c-FOS expression thereby promoting apoptosis.	[221]
		TRAMP model	Using TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, it was demonstrated that oral administration of apigenin at doses of 20 and 50 μg/mouse/day, 6 days per week for 20 weeks, significantly decreased tumor progression of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver. Administration of apigenin resulted in increased levels of E-cadherin and decreased levels of nuclear β-catenin, c-Myc, and cyclin D1.	[222]
		DU-145 cell lines	Apigenin was found to suppress insulin-like growth factor-I receptor signaling in human prostate cancer cells.	[223]
		DU-145 cell lines	Apigenin suppressed the proliferation and inhibited the migration and invasive potential of the DU145 prostate cancer cells in a dose- and time-dependent manner.	[224]
		Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model	Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway and also by blocking β-catenine signaling.	[225]
		LNCaP cells	Exposure of apigenin to hormone sensitive LNCaP cells brought about apoptosis in them by inhibiting casein kinase 2(CK2) activity in the same.	[226]
		PC-3 cells	Apigenin induce apoptosis in prostate cancer cells by modulating ubiquitin mediated proteasomal system to rescue estrogen receptor‑β (ER-β) from degradation.	[227]
2.	Liver cancer	H4IIE hepatoma cells	C8-prenylation of apigenin enhances the cytotoxicity and induces apoptotic cell death in H4IIE hepatoma cells without affecting anti-oxidative properties	[228]
		Hepatocellular carcinoma Hep G2 cells	Apigenin exhibited cell growth inhibitory effects which were due to cell cycle arrest and down regulation of the expression of CDK4 with induction of p53 and p21 protein respectively. The results also suggest that ROS generated through the activation of the NADPH oxidase may play an essential role in the apoptosis induced by apigenin in HepG2 cells.	[229]
		H411E hepatoma cells	Addition of prenyl group at 8C on apigenin increases its cytotoxicity and induces apoptosis in H411E hepatoma cells.	[230]
		Doxorubicin hepatocellular carcinoma BEL 7402/ ADM cells	Apigenin sensitisesdoxorubicin resistant BEL 7402 cells to doxorubicin and increases intracellular concentration of doxocubicin. Apigenin imparts its effect by downregulating Nrf-2 expression at both the mRNA level and protein level through downregulating PI3K/Akt pathway.	[231]
		Hep G2 cells	Apigenin was found to induce apoptosis in Hep G2 cells by reducing expression of CDK4, enhancing the expression of p53 and activating p21/WAF1 pathway. This was in turn associated with cell cycle arrest in G2/M phase.	[232]
		Wistar albino rats with induced hepato-carcinogenesis	Results have also shown in vivo protective effects of apigenin against NDEA induced and phenobarbitol promoted hepatocarcinogenesis in Wistar albino rats. Apigenin treatment at 25 mg/kg body weight for two weeks showed protection against the oxidative stress and DNA damage caused by the NDEA.	[233]
		HeLa cell line	Findings from the study suggested that apigenin inhibited SOD activity without altering its concentration in the culture cells. But, apigenin as well as paclitaxel at the same time brought about apoptosis of the cancer cell line via over expression of caspase-2.	[234]
3.	Adrenal cancer	H295R human adenocortical cancer cells	Laboratory studies using various flavonoids against adrenocortical cancers have shown induction and inhibition of aromatase (CYP19) associated with increased intracellular cAMP concentrations.	[235]
			Further investigation of plant flavonoids on cortisol production in H295R cells indicate that cells exposed to apigenin results in a decrease in cortisol production, 3β-HSD II and P450-c21 activity.	[236]
4.	Hematologic cancer	Leukaemia HL-60	Apigenin was shown to be markedly more effective than other tested flavonoids in inducing apoptosis in human leukaemia cells through cytochrome-c release and activation of caspase-9 and caspase-3.	[237]
		Human leukaemia cell lines	Apigenin in different leukemia cell lines resulted in selective antiproliferative and apoptotic effects in monocytic and lymphocytic leukemias; this selective apoptosis is mediated by induction of protein kinase C delta.	[238]
		Human platelets	Apigenin inhibits platelet adhesion and thrombus formation and synergizes with aspirin in the suppression of the arachidonic acid pathway	[239]
		U937 cells	Apigenin and other flavones but not the isoflavones or flavanones tested were shown to induce apoptosis in U937 cells.	[240]
		Infant leukaemia	Another study evaluated the role of dietary bioflavonoids in inducing cleavage in the MLL gene, which may contribute to infant leukemia.	[241]
5.	Skin cancer	A375 and A549 melanoma cell lines	Lycopodium clvatum extract having apigenin as a parent compound exerted apoptosis in melanoma cell lines by modulating caspase 3, 9, PARP, bax, bcl-2 and cyt-c activity and thus, showed to have anti-cancer property.	[67]
		Mice keratinocyte cell lines	Apigenin suppresses the UV B-induced COX-2 expression (a key enzyme which converts the arachidonic acid to prostaglandins and its over-expression results in carcinogenesis) and mRNA in mouse and even in human keratinocyte cell lines.	[146, 147]
		Benzo(a)pyrene and UV-B induced skin tumor in mouse	Apigenin loaded with poly (lactic-co-glycolide) (PLGA) nanoparticles (Nap) was found to produced far better effects than apigenin alone against Benzo(a)pyrene and UV-B induced skin tumor and mitochondrial dysfunction in rat model.	[176]
		Mouse epidermal JB6 P+ cells	Apigenin can restore the silenced status of Nrf2 in skin epidermal JB6 P+ cells by CpG demethylation coupled with attenuated DNMT and HDAC activity, thus suggesting the therapeutic role of apigenin in preventing skin cancer.	[242]
		Murine B16 melanoma cells	Apigenin along with hyperosid and icariin were found to significantly increase cellular melanin content without affecting cell proliferation.	[243]
		Mice SHK-1 cells	Apigenin is effective in the prevention of UVA/B-induced skin carcinogenesis in SKH-1 mice.	[244]
		Mice Keratinocytes	In other studies with exposure of mice keratinocytes to apigenin it was seen that apigenin induced G1/S and G2/M cell cycle arrest and accumulation of the p53 tumor suppressor protein with increased expression of p21/WAF1. This arrest was accompanied by inhibition of p34 (cdk2) kinase protein level and activity, which was found to be independent of p21/WAF1.	[245, 246]
		Human diploid fibroblast cells	Apigenin produced G1 cell-cycle arrest by inhibiting cdk2 kinase activity and inducing p21/WAF1 in Human diploid fibroblast cells.	[247, 248]
		Tumorigenic epidermal keratinocytes xenograft in mice	Increased expression of Thrombospondin-1(TPS-1), RNA binding protein HuR and reduction in COX-2 and HIF-1α production by apigenin controls UVB-induced tumorigenic epidermal keratinocytes xenograft in mice.	[249]
		Female SENCAR mice	Skin tumorigenesis initiated by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by 12-O-tetradecanoyl phorbol-13-acetate (TPA) in SENCAR mice, was found to be attenuated by topical application of apigenin dose dependently. Anti-tumorigenic effect might be attributed to the inhibition epidermal ornithine decarboxylase enzyme by apigenin treatment.	[250]
		Human HL-60 and mouse C-50 and 308	Exposure of human HL-60 and mouse C-50 and 308 cell lines to apigenin induced G2/M cell cycle arrest by preventing the accumulation of Cyclin B and also by inhibiting the p34^cdc2 H kinase activity.	[251]
		Normal human Keratinocyte cell lines	In this study apigenin and curcumin were found to inhibit differentiation of keratinocytes via modulating MAPK pathway and reducing AP-1 expression. EGCG on the other hand showed inverse effect as evidenced by increased keratinocyte morphological differentiation. This is due to increased expression of involucrin, transglutaminase type-1 and caspase 14.	[252]
6.	Brain cancer	SH-SY5Y neuroblastoma cells	SH-SY5Y neuroblastoma cells when exposed to flavonoid apigenin were found to undergo apoptosis associated with an increase in Bax:Bcl-2 ratio, cyt c release and activation of calpain, caspase 3,9 and 12 .	[91]
		Human neuroblastoma cells.	Apigenin has shown to induce caspase-dependent, p53-mediated apoptosis in human neuroblastoma cells.	[253]
		PC 12 cell line (Neuron like cells)	Oxygen and glucose deprived reperfusion injury (OGD/R) significantly decreased cell viability, mitochondrial membrane potential, mRNA levels of antioxidant and detoxifying enzymes and Nrf2 protein expression, while elevated the release of LDH, cell apoptosis, intracellular ROS, P53 protein expression and also upregulated downstream genes in PC12 cells. However, treatment of cells with apigenin has reversed the effects.	[254]
		T98G and U87MG	Glioblastoma cell lines T98G and U87MG were found to undergo apoptosis when treated with apigenin thus reducing cancer progression. However, no apoptotic effect was observed in normal human astrocytes.	[255]
7.	Thyroid cancer	UCLA RO-81A-1 (ARO) anaplastic carcinoma cell line	Inhibitory effect of apigenin on ARO cell proliferation was associated with inhibition of both EGFR tyrosine autophosphorylation and phosphorylation of its downstream effector MAPK.	[256]
		FTC 133 transfected with hNIS	When human follicular thyroid cancer cell lines (FTC 133), stably transfected with human Na+/I- symporter (hNIS) were treated with apigenin a reduction in the expression of NIS mRNA was observed. This study opens up the gateway for the radioiodine treatment of thyroid cancers.	[257]
		FRO anaplastic thyroid carcinoma cells	Apigenin is found to induce apoptosis via increased c-myc expression and by simultaneous phosphorylation of p38 and p53 tumor suppressor genes.	[258]
8.	Ovarian cancer	HO-8910PM cells	Apigenin inhibited the activity of MAPK and PI3K in human ovarian carcinoma HO-8910PM cells.	[259]
		SKOV3 and SKOV3/TR cell lines	Cirumvention and antiproliferative effect of apigenin in taxol resistant SKOV3/TR and SKOV3 ovarian cancer cell lines is due to the inhibition of IL-6/STAT3 axis and targeting Axl and Tyro3 receptor tyrosine kinases.	[260]
		OVCAR-3 and A2780/CP70 cell lines	On treatment with apigenin inhibition of tumor angiogenesis was observed, which was associated with the decrease in the levels of hypoxia inducible factor -1α (HIF-1α) and vascular endothelial growth factor (VEGF) in tumor tissues via: PI3-K/Akt, HDM2/p70S6K1 and p53 pathways.	[261,262]
		A2780 cell lines	Apigenin reduced the tumor progression in ovarian cancer cell line A2780 by acting as an inhibitor of differentiation or DNA binding protein 1 (Id1).	[263]
9.	Colo- rectal cancer	Endometrial cancer cells	Analysis of DNA in endometrial cancer cells treated with phyto-estrogenic compounds including apigenin using comparative genomic hybridisation microarrays have suggested that apigenin may play a role in the treatment of endometrial cancer and in the treatment of postmenopausal women.	[264]
		HT-29 and HCT- 15	Treatment of colorectal cell lines HT-29 and HCT-15 with apigenin resulted in anti-proliferative and apoptotic effects characterized by biochemical and morphological changes. Inhibition of Rb phosphorylation and up-regulation of p21 regulation of p21 led to simultaneous suppression of cyclins D1 and E which indicated the onset of senescence.	[265]
		HCT-116 cell line	Apigenin resulted in G2/M phase arrest of HCT-166 cells by suppressing the expression of cyclin B1, cdc-2 and cdc-25. In addition expression of cell cycle inhibitors, such as p53 and p53-dependent p21CIP1/WAF1 was reduced after apigenin treatment.	[266]
		SW480 and Caco-2	Apigenin along with the combination of its 5 analogues (acacetin, chrysin, kampherol, luteolin and myricetin) at different concentrations inhibit SW480 and Caco2 cell line proliferation by arresting them at G2/M pase of cell cycle.	[267]
		HT-29 andSW620 cell lines	Apigenin induces G2/M arrest in colon cancer cell lines by downregulating expression of cyclin dependent kinase 1(CDK1) through binding and inhibition of ribosomal protein S9.	[268]
10.	Lung cancer	B16-BL6 murine melanoma cells	In vivo administration of apigenin was effective in inhibiting melanoma lung tumor metastasis in B16-BL6 murine melanoma metastasis model.	[269]
		A549 and H460 cell lines	Apigenin downregulates Axl expression, which subsequently results in the inhibition of A-549 and H460 cell line proliferation, through an increase in p21 and decrease in (X linked inhibitor of apoptosis protein) XIAP expression.	[270]
		Human lung squamous carcinoma (SQ-5) cells	Radiosensitising sphere forming human lung squamous carcinoma (SQ-5) cells, when incubated with apigenin underwent apoptosis and necrosis in a dose and time dependent manner. This was due to the over expression of WAF/p21 and decreased expression of Bcl-2 genes.	[271]
		Lewis lung carcinoma (LLC), C-6 glioma and DHDK-12 cell lines	In contrast to the high in vitro sensitivity of LLC, C-6 glioma, DHDK-12 colonic cancer and endothelial cancer cell lines to 50 mg/kg/day (for 12 days) of apigenin, the in vivo response in rats was found to be negligible. The inhibition was achieved due to cytotoxicity and anti-angiogenin effect of apigenin.	[272]
		B57BL/6N mice model injected with B16-BL6 murine myeloma cells	Apigenin along with two other flavonoids at a concentration of 50mg/kg (for 6 to 14 days) were found to inhibit VCAM-, TNF-α and ICAM-1 expression in a dose-dependent manner in human umbilical vein endothelial cells (HUVEC) and murine pulmonary endothelial cells.	[273]
11.	Bladder cancer	T-24 cell line	Treatment of T-24 cells with apigenin was associated with an increase in the phospho-p53, p53, p21, and p27 levels, and a decrease in the Cyclin A, Cyclin B1, Cyclin E, CDK2, Cdc2, and Cdc25C levels thereby, blocking cell cycle progression during G1/S and G2/M. In addition, apigenin increases the Bax, Bad, and Bak levels, but reduces the Bcl-xL, Bcl-2, and Mcl-1 levels, which subsequently triggers the mitochondrial apoptotic pathway.	[274]
		T-24 cell line	Results demonstrated that apigenin suppressed proliferation and inhibited the migration and invasion T-24 bladder cancer cells in a dose- and time-dependent manner, which was associated with induced G2/M Phase cell cycle arrest and apoptosis. The mechanism involves PI3K/Akt pathway and Bcl-2 family proteins. Increase in caspase-3 activity and PARP cleavage guides the cell towards apoptosis.	[275]
12.	Breast cancer	HER2/neu overexpressing breast cancer cells	HER2/neu overexpressing breast cancer cells are known to cause breast cancer by inhibiting apoptosis through activation of PI3K and Akt/PKB signalling pathways. Apigenin reduced HER2/neu gene expression without affecting the cells expressing basal levels of HER2/neu by inhibiting PI3K activity and consequently inhibiting Akt kinase activity.	[276, 277]
		MDA-MB 453 cell line	Apigenin has shown to induce apoptosis through cytochrome-c release and rapid production of DNA fragmentation factor 45 in MDA-MB-453 human breast cancer cells	[278]
		MCF-7 cell line	PKC-activating phorbol ester (PMA) prevents apoptosis by activating cellular signaling pathways such as MAPK and PI3K and suppression of TNF-α in MCF-7 breast cancer cells. Apigenin was found to induce apoptosis in these breast cancer cells by suppressing the PMS mediated AP1 activity which in turn is due to the suppression of MAPK and PI3K pathways.	[279]
		SK-BR 3 breast cancer cells	Apigenin induces G 2/M arrest associated with the modulation of p21 (Cip1) and Cdc2 and activates p53-dependent apoptosis pathway in human breast cancer SK-BR-3 cells.	[280]
		MDA-MB – 231cell line	The effect of apigenin on protease-mediated invasiveness was evaluated in estrogen-insensitive breast tumor cell line MDA-MB231 showing that apigenin strongly inhibit tumor cell invasion.	[281]
		MDA-MB – 453 cell line	Apigenin inhibited the proliferation of MDA-MB-453 cells by inhibiting JAK2-STAT3 pathway and inducing apoptosis via up-regulation of cleaved caspase 8 and caspase 3.	[282]
		MB-468	Decreased proliferation of MB-468 cell line was observed after treatment with apigenin. This was due to the inhibition of Akt (Protein kinase B), which is essential for tumor progression and arrest of cells in G2/M phase.	[283]
		SKBR3 breast cancer cells	Apigenin induces caspase-dependent apoptosis by inhibiting signal transducer and activator of transcription 3 (STAT 3) signaling in HER2-overexpressing SKBR3 breast cancer cells.	[284]
		MCF-7 cell line	Apigenin inhibits growth and induces G2/M arrest by regulating cyclin-cdk complexes and ERK-MAP Kinase pathway in given cell lines	[285]
		MCF 7 breast cancer cells	Apigenin targets both ERalpha-dependent and ERalpha-independent pathways on estrogen-responsive, anti-estrogen sensitive MCF7 breast cancer cells and growth inhibitory effect on two MCF7 sub-lines with acquired resistance to anti-estrogens viz. tamoxifen or fulvestrant.	[286]
		MCF-7, T47D and MDA-MB-435 breast cancer cells	Apigenin has been shown to stimulate the proliferation of MCF-7 and T47D cells estrogen receptor alpha (ER alpha-positive), but do not stimulate the proliferation of an ER alpha negative cell line MDA-MB-435 cells.	[287]
		MDA-MB 231 breast cancer cells	Apigenin induces apoptosis by the activation of caspase 3, 7 and poly (ADP-ribose) polymerase cleavage and also by inhibiting proteasomal chymotrypsin-like activity in cultured MDA-MB-231 cells and also in MDA-MB-231 xenografts.	[65]
			Apigenin inhibits hepatocyte growth factor-induced MDA-MB-231 cells invasiveness and metastasis by blocking Akt, ERK and JNK phosphorylation and also inhibits clustering of β-4-integrin function at actin rich adhesive site.	[288]
		Mammary Adeno-carcinoma (AMN3) bearing mice	After 24 days of oral administration of apigenin at a dose of 300 mg/kg body weight, a significant reduction in the volume of mammary adenocarcinoma was found in treated animals, along with the decrease in lipid peroxidation and a subsequent increase in reduced glutathione content.	[289]
		SK-BR and MCF-7/HER2 cells	Apigenin derived from extra virgin olive oil was able to suppress the expression of lipogenic enzyme fatty acid synthase in SKBR and MCF-7/HER2 cells	[290]
13.	Cervical cancer	HeLa cell lines	Apigenin inhibited cell growth, G1 growth phase arrest and induced p53 dependent apoptosis and was associated with a marked increase in the expression of p21/WAF1 protein with the induction of Fas/APO-1 and caspase-3 expression. Apigenin also decreased the expression of Bcl-2 protein, an antiapoptotic factor.	[291]
		HeLa C-43 cell lines	The effect of apigenin on cell proliferation was less pronounced especially at low apigenin concentration, whereas its influence on cell motility correlated with the reduction of the invasive potential of HeLa C 43 cells.	[292]
		Sphere-forming cells (SF)/ HeLa cells	Results suggested that apigenin inhibits the self-renewal capacity of HeLa derived SFCs through down-regulation of protein kinase casein kinase 2 (CK2α) expression.	[293]
14.	Gastric cancer	SGC-7901 and gastric mucosa epithelial cells (GES-1)	Apigenin modulated growth inhibition in SGC- 7901 cell lines by inducing apoptosis	[294, 295]
		HGC-27 and SGC-7901 cell lines	Apoptosis was induced in gastric carcinoma cells through mitochondrial signalling pathway after apigenin treatment.	[296]
		-	Apigenin is able to reduce cancer cell glucose uptake, inhibit remodeling of the extracellular matrix, inhibit cell adhesion molecules that participate in cancer progression, and oppose chemokine signaling pathways that direct the course of metastasis into other locations, thereby suggesting its anti carcinogenic potential against gastric carcinoma.	[297]
		BGC823 cells	Human gastric carcinoma cells BGC823 when exposed to flavonoid apigenin were found to undergo apoptosis associated with a reduction in Bcl-2 expression and an increase in the expression of Bax, cyt c release and activation of caspase 3 and 9.	[298]
		Mongolian Gerbils	The study reveals the protective effect of apigenin on the progression of Helicobacter pylori induced atrophic gastritis and gastric cancer in Mongolian gerbils.	[299]
		Human gastric cancer cell line SGC-7901	In this study apigenin was found to inhibit proliferation of gastric cancer cell lines by inhibiting PKB/Akt signalling and anti-apoptotic protein Bad. Authors also reported that apigenin promoted apoptosis in the cancer cells by specific phosphorylations on Akt and Bad without affecting their expression levels.	[300]
15.	Leukaemia cell lines	K562 human chronic leukaemia cells	Apigenin induced erythrocyte differentiation in K562 human chronic leukaemia cells via 2-3 double bond and hydroxyl group in its moiety.	[301]
		K562 and K562/IMA3 cell lines	The study concluded that apigenin inhibits cell proliferation and induces apoptosis by up-regulating the activity of caspase- 3 and arresting the cells in G2/M phase of cell cycle repectively.	[302]
		Myeloma cell lines U266 and RPMI 8226	Apigenin was found to kill MM cells by targeting the trinity of CK2-Cdc37-Hsp90. By depleting these kinases, apigenin suppresses both constitutive and inducible activation of STAT3, ERK, AKT and NF-кB.	[303]
		Mouse macrophage ANA-1 cells	Apigenin increased the level of intracellular ROS, downregulated the expression of Bcl-2 and upregulated the expression of caspase-3 and caspase-8 in ANA-1 cells. Furthermore, apigenin downregulated the expression of phospho-ERK and phospho-JNK and upregulated the expression of phospho-p38, which leads the cell towards apoptosis.	[304]
16.	Multidrug resistant (MDR) tumor cells	MDR tumor cells over expressing ABC transporters, BCRP/ ABCG2, P-glycoprotein /ABCB1 and ABCB5.	Apigenin overcomes multi drug resistance by increasing cellular uptake of doxorubicin and synergistic inhibition of cell viability in combination with doxorubicin or docetaxel in multidrug-resistant cells.	[305]
17.	Pancreatic cancer	BxPC 3 and PANC 1	Flavonoid apigenin induced apoptosis in human pancreatic cancer cells by arresting them at G2/M stage through inhibition of GSK-3β/NF-кB signaling cascade. Apigenin highly upregulated the expression of cytokine genes IL-17F, LTA, IL-17C, IL-17A, and IFN-B1 in BxPC-3 and PANC1 cells, thereby driving them towards apoptosis.	[306]
		CD18 and S2-013 cell lines	Apigenin inhibits Glucose transporter GLUT-1 and PI3-K/Akt pathway in human pancreatic cancer cell lines and thus, evoke apoptosis in them.	[307]
		Mia Paca-2 and As PC-1 cell lines	A combination of gemcitabine and apigenin was found to enhance apoptosis in pancreatic cancer cell lines via: NF-кB and Akt pathway.	[308]
		PC cell xenograft in athymic nude mice	Inhibition of pancreatic cancer cell growth was observed in athymic nude mice xenograft on treatment with apigenin. Apigenin down-regulates basal as well as TNF-α-induced NF-κB DNA binding activity, NF-κB transcription activity, inhibitor of κB (IκB)-α phosphorylation, translocation of p65 and p50, accompanied with the blockade of IκB kinase (IKK)-β activity.	[309]
		Pancreatic stellate cells (PSC)	Through in vitro and in vivo studies it was demonstrated that apigenin and its analogs (HJ05-61) and HJC05-100 inhibit PSC proliferation and induced apoptosis in the concerned cells at concentrations as low as 13 µM, 4 µM and 1 µM respectively.	[310]
18.	Others	Retinal pigment epithelial cells (RPE)	Apigenin along with other flavonoids have shown to induce cellular necrosis in RPE cells by decreasing the expression of VEGF and were also able to induce apoptosis by reducing the phosphorylation of Src kinase/Akt modulators.	[311]
		Human embryonic kidney (HEK) 293 cells	Flavonoids namely quercetin, kaempferol and apigenin inhibited organic anion transported polypeptide 1A2 (OATP1A2) and 2B1 (OATP2B1) mediated transport of two anti-allergic drugs fexofenadine and atorva statin. This was determined by dixon plot analysis using BSP as substrate.	[312]
		Laryngeal carcinoma Hep2 cells	The study revealed that apigenin at a concentration 50 mM reduced the expression of GLUT-1 and down reulated PI3K/Akt pathway thereby promoting better action of cisplatin and preventing chemotherapeutic resistance to laryngeal carcinoma.	[313]

Table 6. Molecular targets of apigenin.

Gene expression	Protein kinases	Transcription factors	Enzymes	Membrane proteins	Others
Cyciln D	Ikk/IkB kinase	STAT-3	FTPase	VCAM	Bcl-2
Cyclin A	JAK	NF-кB	GST	ICAM	Bcl-xl
Cyclin B1	Src	AP-1	GSH-Px	VEGF	EGFR
Cyclin E	JNK	PI-3	GSH-R	EGFR	Bax
5-LOX	HER-2	Egr-1	CAT	MRPs	p53
COX-1	Akt/PKB	Erβ	SOD	MMPs	p21
COX-2	PKA	CBP	ALT	FAK	p27
P53	PKC	PPAR	ALP	IGF-1R	TRAIL
P21	PI3K	EpRE	GGT		APC
p27	MAPK	β-catenin	LDH		PTEN
iNOS		Nrf-2	AST	VEGF	IGF-1
IL-6		HIF-1α	XO		XIAP/IAP
IL-5		Elk-1	HO		β-CTF
IL-8		GATA-3	ODC		BDNF
IL-12			Cyt-P450		TGF-β
IL-17			Aromatase		HO-1
TNF-α			Caspase 3,9
c-Fos			AChE
			BChE

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