Table 1.

In vitro preclinical studies regarding the anticancer molecular mechanisms of genistein.

Type of cancer		Cancer cell lines	Potential anticancer mechanisms	Ref
Brain tumors	Neuroblastoma	IMR-32 SK-N-BE2	↑Apoptosis, ↓cell viability, ↑Myd88, ↑Beclin 1, ↑LC3 II, ↑TLR4, ↑autophagy, ↓mTOR, ↓p62	[52]
		SK-N-SH	↑Cell cycle arrest at phase G2/M, ↓proliferation, ↑Akt, ↑CHD5, ↑p53, ↓neuroblastoma growth, ↓tumor microvessel formation, ↓DNMT3b, ↑ERE, ↑luciferase, ↑MEK	[53–55]
		SK-N-DZ	↑Apoptosis, ↑FasL, ↑TNFR-1, ↑TNF-α, ↑FADD, ↑caspase-8, ↓cell proliferation, ↑PARP, ↑DFF45 cleavage, ↑apoptosis	[57]
		SH-SY5Y (N-Myc nonamplified) SK-N-DZ (N-Myc amplified)	↑Suppression of survival and angiogenic pathways: cleavage of Bid to tBid, ↓hTERT, ↓VEGF, ↓NF-κB, ↓c-IAP2, ↓MDR, ↓N-Myc, ↓FGF2, ↓p-Akt, ↑apoptosis	[58]
		SH-SY5Y SK-N-BE2	↑Apoptosis, ↓tumor weight, ↓volume, ↑Smac, ↑Bax, ↓Bcl-2, ↓BIRC, ↓AIF, ↓caspase-3, ↓VEGF, ↓FGF2, ↓NF-κB	[59]
		SK-N-BE2	↑Apoptosis, ↑Bax, ↓Bcl-2, ↑mitochondrial release of cytochrome c, ↑AIF, ↑Smac, ↑Bax : Bcl-2 ratio, ↓N-Myc, ↑NF-κB, ↑calpain, ↑caspase-3, ↑caspase-8, ↓SBDP	[60–62]
	Glioblastoma Medulloblastoma	Glioblastoma A172, KNS60, U251MG Medulloblastoma ONS76	↓Cell growth, ↑cell arrest at the G2/M phase, ↑DNA damage, ↓telomerase, ↑telomere shortening	[67]
	Pituitary cancer	Human prolactinoma cells	↑Apoptosis, ↑percentage of cells in phase G1, ↓DNA synthesis, ↓cell proliferation of cultured pituitary cells	[69]
		Mouse AtT-20 Rat anterior pituitary cells	↓Proliferation at the G0/G1 phase and G2/M phase, ↑apoptosis	[70]
Breast cancer		T47D MCF-7-C3	↓CIP2A, ↓E2F1, ↑apoptosis, ↑growth inhibition, ↑proteasomal degradation, ↑transcriptional suppression	[71]
		MCF-7 MDA-MB-231	↑ABCC1, ↑ABCG2, ↑apoptosis, ↓p-Akt, ↓IGF-1R, ↓Bcl-2-associated X protein-protein ratio	[72]
		BCSCs	↓CD44+/CD24-/ESA+, ↑PI3K/Akt, ↑MEK/ERK, ↑G2/M cell cycle arrest, ↑apoptosis, ↑BRCA1, ↑ATR complex, ↑DNA damage, ↓TNBC	[74]
		Hs578t MDA-MB-435	↑Apoptosis, ↓cell viability, ↑miR-23b	[75–79]
		MCF-7 T47D	↓IGF-1R-PI3K/Akt, ↓cell proliferation, ↓Bcl-2/Bax, ↓mRNA, ↑apoptosis, ↓Akt, ↓HOTAIR	[84, 86]
		MCF-7/Adr	Genistein combined with doxorubicin: ↑intracellular accumulation of doxorubicin, ↑apoptosis, ↑cell cycle arrest, ↓HER2/neu expression	[87]
		MCF-7	↑Ribose 5-phosphate, ↑6-phosphogluconate, ↑pentose phosphate pathway, ↓glutamine, ↓glucose uptake, ↓protein biosynthesis	[89–94]
Lung cancer		A549	↑Caspase-3/9, ↑apoptosis, ↓MET, ↑miR-27a	[97]
		A549 MRC-5	Radiosensitizing effect, ↑oxidative stress, ↓oxidative damage, ↑mRNA, ↑GSH, ↑Nrf2, ↑HO-1	[98]
		A549, NCI-H460 (H460), ABC-1	↑TSA, ↑histone or nonhistone protein acetylation, ↑histone H3/H4 acetylation, ↑expression of protein p300	[99]
		A549	Genistein combined with ATRA, ↓ICAM-1, Bcl-2, ↓MUC1, ↓Bcl-2, ↓Bax, ↓p-ERK1/2, ↓Cdk4, ↓Rb, ↓metastatic potential	[100]
		H446	↑Apoptosis, ↓cell proliferation, ↓FOXM1 protein, ↓proliferation	[101]
		A549	↓Cyclin D1, ↓Cdk4, ↑p15, ↑p21, ↑p27l, ↑Rb protein phosphorylation, ↑p53, ↑caspase-3, ↓TNFR-1, ↑apoptosis	[56]
Gastrointestinal cancers	Salivary gland cancer	SACC-83	↓Bax, ↓survivin, ↓Bcl-2, ↓protein tyrosine kinase, ↓cyclin D1, ↓cyclin B1, ↓Cdk4, ↓Cdk1, ↑G2/M cell cycle arrest	[106]
	Esophageal cancer	TE-2 (p53, wild) TE-1 (p53, mutant)	↑Radiosensitivity of cell lines, ↓p42/p44, ↑Akt/PKB, ↑poly(ADP-ribose) polymerase, ↑Bax, ↓Bcl-2	[111, 112]
	Gastric cancer	AGS MKN45	↓Chemoresistance to 5-FU and cisplatin, ↓ERK1/2, ↓ABCG2, ↓tumor mass, ↓CD44, ↓Gli1, ↓Gli1 siRNA	[113]
		BGC-823	↓p34(cdc2), ↑Tyr15, ↑G2/M cell cycle arrest, ↓COX-2, ↑apoptosis	[114]
		SGC-7901	↓Ser642, ↑PTEN, ↓CENPF, ↓KIF23, ↓KIF22, ↓KIF20A, ↓KIF11, ↓FOXM1, ↓cdc25B, ↓cyclin B, ↓Cdk1, ↑p27Kip1	[115–120]
	Liver cancers	PLC/PRF5	↑Apoptosis, ↑G2/M cell cycle arrest	[125]
		HepG2	↑MRP2 mRNA, ↑P-gp, ↓miR-379	[126]
		HepG2/C3A	Long term: ↑CYP1A Short term: ↓YP1A	[127, 128]
		BNL CL2, Huh7, HepG2, HA22T	↓MMP-9, ↓NF-κB, ↓P-1, ↑AP-1, ↓JNK, ↓ERK, ↓NF-κB, ↑phosphatidylinositol/ERK3-kinase/Akt	[129]
		SMMC-7721, HepG2, Bel-7402	↑α-Catenin, ↑E-cadherin, ↓vimentin, ↓N-cadherin, ↓mRNA, ↑EMT, ↑TGF-β, ↓autotaxin, ↓COX-2, ↓ABCA3, ↓CD154	[130]
	Pancreatic cancer	MIA PaCa-2	↓miR-27a, ↓cell growth, ↓invasion, ↑apoptosis, ↓onco-miR-223	[134, 135]
		AsPC-1, MIA PaCa-2	↓TGF-β1, ↓E-cadherin	[137]
	Colon cancer	HCT116	↓MMP-2, ↓FLT4, ↑G2/M cell cycle arrest	[140, 142, 143]
		HT-29, LoVo	↑Apoptosis, ↓NF-κB, ↓Bcl-2, ↑Bax, ↓β-catenin	[141, 144]
		SW480, HCT116	↑G2/M cell cycle arrest, ↑p21waf1/cip1, ↑GADD45α, ↑ATM/p53, ↓cdc2, ↓cdc25A, ↓H3Ac, ↑Sfrp2, ↑Sfrp5, ↑Wnt5a	[145, 146]
		DLD-1, SW480, SW1116	↓EGF, ↑FOXO3, ↑p27Kip1	[148, 150, 151]
Urinary tract cancers	Kidney cancer	HK-2	↓PTH, ↑α-SMA, ↓CTGF, ↓mRNA, ↑E-cadherin	[153]
		A498, 786-O, Caki-2	↓miR-1260b, ↓DKK2, ↓Sfrp1, ↓Smad4	[154]
		A498, HEK-293, ACHN	↑2H3K4, ↑acetylated histones 3 and 4, RNA polymerase II, ↑3H3K4	[150, 155, 156]
	Bladder cancer	BDEC, TCCSUP	↑DNA damage, ↑cell growth, ↑cycle arrest of the G2/M phase, ↑apoptosis	[159–161]
		253J B-V	↓Growth of cells	[237]
	Prostate cancer	LAPC-4, LNCaP, PC-3	↓ER-β	[164–166]
		PC-3, DU145	↓miRNA-1260b, ↓Smad4, ↓Sfrp1	[167]
		C4-2B, ARCaPM, PC-3, PC-3-luc	↑Bax, ↓mCRPC growth	[169]
		DU145, PC-3	↑miR-34a, ↓HOTAIR, ↓miR-151	[170] [78
		C4-2B, LNCaP	↓Cell proliferation, ↑apoptosis	[171]
Genital cancers	Endometrial cancer	MES-SA, MES-SA-Dx5, SK-UT-1	↑DKK1, ↑p53, ↓Bax, ↓phospho-MEK, ↓β-catenin, ↓p27, ↑DNA fragmentation, ↑caspase-3	([179], [180])
		Ishikawa	↑DR5, ↑DR4, ↓caspase-8, ↓caspase-3, ↓PARP	[181]
		UtLM	↓TGF-β, ↓activin A, ↓Smad3	[183]
		ELT-3	↑PPARγ	[187]
Bone cancer	Cervical cancer	HeLa	↑Apoptosis, ↑CHOP, ↑p-p70S6K1, ↑NF-κB, ↑p-4E-BP1, ↑p-mTOR, ↑p-Akt, ↓TIMP-1, ↓survivin expression	[188, 191, 192, 196]
		TC-1	↑IFN-γ	[193]
		CaSki, HeLa	↓ERK1/2, ↓p38 MAPK	[194]
	Ovarian cancer	BG-1	pSmad3, ↓TGF-β, ↓EMT, ↓BPA, ↓E2, ↓TGF-β	[197]
		OCSLCs	↓FOXM1, ↓CD133, ↓ALDH1, ↓CD44	[198]
	Testicular cancer	TM4	↑Caspase-3, ↑necrosis, ↑apoptosis, ↑CPP32	[200, 201]
		MG-63	↑PPARγ	[202]
	Osteosarcoma	MNNG/HOS	↑Akt, ↓NF-κB	[203]
Skin cancer	Melanoma	C918	↓VE-cadherin mRNA, ↓Bcl-xL, ↓Bcl-2, ↑Apaf-1	[212–216]
		B164A5	↓Tumor weight, ↓volume, ↓quantity of melanin	[210]
		LiBr	↓Caspase-3, ↑apoptosis	[119]

Abbreviations: DNMT: DNA methyltransferase; TNF-α: tumor necrosis factor alpha; FADD: Fas-associated death domain; SF: sorafenib; 4-HPR: retinoid N-(4-hydroxyphenyl) retinamide; BIRC: baculovirus inhibitor of apoptosis repeat containing; AIF: apoptosis-inducing factor; VEGF: vascular endothelial growth factor; FGF2: fibroblast growth factor 2; SBDP: alpha spectrin to 145 kD spectrin breakdown product; CIP2A: cancerous prohibitor of protein phosphatase 2A; ABCC1: ATP-binding cassette subfamily C member 1; ABCG2: ATP-binding cassette superfamily G member 2; BCSCs: breast cancer stem cells; Bcl-2: B-cell lymphoma 2; HOTAIR: HOX transcript antisense intergenic RNA; miR-27a: microRNA-27a; HO-1: heme oxygenase-1; TSA: trichostatin A; ATRA: all-trans retinoic acid; Gli1: glioma-associated oncogene; siRNA: small-interfering RNA; miRNA: microRNA; Tyr15: phospho-cdc2; Ser 642: phospho-Wee1; PTEN: phosphatase and tensin homolog on chromosome 10; mRNA: messenger ribonucleic acid; MMP-9: matrix metallopeptidase-9; TPA: 12-O-tetradecanoylphorbol-13-acetate; JNK: c-Jun N-terminal kinase; ERK: extracellular signal-related kinase; MMP-2: matrix metalloproteinase-2; FLT4: Fms-related tyrosine kinase 4; H3Ac: histone H3 acetylation; FOXO: transcription factors of the forkhead box; CTGF: connective tissue growth factor gene; DKK1: Dickkopf-related protein 1; phospho-MEK: phosphorylated mitogen-stimulated protein kinase kinase; TIMP-1: tissue inhibitor of metalloproteinase-1; IFN-γ: interferon γ; FOX: forkhead box M1.