. 2022 Nov 16;15(11):1418. doi: 10.3390/ph15111418

Table 1.

Anticancer effects of daidzein and its metabolites including equol based on in vitro studies.

Type of Cancer	Cell Lines	Effects	Mechanisms	Concentration	References
Osteosarcoma	143B and U2OS	Induces apoptosis	↓ proliferation and migration of 143B and U2OS osteosarcoma cells, ↑ %age of S phase cells, ↓ %age of G0/G1 phase cells, ↓ p-Src-ERK, ↓ p-Src, ↓ p-ERK, No change in expression levels of Src, JNK, p-JNK, ERK, p38 and p-p38	Daidzein—0, 10, 20, 50, 100, 200 or 500 µM	[15]
Osteosarcoma	MG-63	Induces apoptosis	↑ ROS, ↓ mitochondrial membrane potential, ↑ apoptosis rate, ↑ cell cycle arrest at the G₂/M phase, ↓ Bcl-2, ↓ Bcl-x and ↓ Baid proteins, ↑ Bim protein	Daidzein—IC₅₀ value of 59.7 µM	[16]
Colon	HT-29	Induces apoptosis	↓ growth of cancer cells, significant increase in cells in the G₀/G₁ phase, ↓ Lipid droplets accumulation, ↓ Perilipin-1, ↓ ADRP and↓ Tip-47 family proteins, ↓ vimentin, ↑ PPAR, ↑ Fas, ↑ FABP, ↑ GPAT3, ↑MTTP, ↓ UCP2. ↓ PI3K, ↑ FOXO3a, ↑ caspase-8	Genistein and Daidzein—0, 25, 50, 100, 200, and 400 μM	[17]
Colon	DLD1, HCT15, COLO205, LOVO, SW480	Induces apoptosis	↓ growth of HCT-15 cells with the expression of ERα and ERβ, ↓ growth of LOVO, and SW480 cells with the ERβ expression, ↑ ERα and ERβ in HCT-15. ↑ ERα and ERβ, ↑ Nrf2	Equol—0, 0.5, 1, 5, 10 μM	[18]
Breast	MCF-7	Induces apoptosis	↑ % age of apoptotic cells, ↑ Caspase 3/7 activity, ↑ Bax, ↓ Bcl2, ↑ ROS, ↓ ERα, ↑ ERβ	Daidzein—IC₅₀—50 µM	[19]
	MCF-7 and T47D	Induces apoptosis	↑ cytotoxic effects towards cancer cells, ↓ NGB, ↑p- AKT, ↑ p38 phosphorylation, ↑ cleaved PARP-1	Daidzein—1–10 µM and Equol 1 μM	[20]
	MCF7 and MCF7/ADR	Enhances the anticancer effect of topotecan (tpt) and reverses BCRP-mediated drug resistance	↑ anti-proliferative effect with TPT on MCF7 and MCF7/ADR cells, ↑ inhibitory effect of TPT on Topo Ⅰ activity, ↑ inhibition of TPT on the catalytic activity of Topo Ⅰ, ↑ cells arresting at the G₂/M phase, ↑ apoptosis rate, ↓ resistance of MCF7/ADR cells to TPT, ↓ ERα and BCRP, ↑ TPT accumulation intracellularly	Daidzein—0, 2.13, 6.25, 12.5, 25, 50, 100, 200 and 400 µM and Topotecan 0, 0.78, 1.56, 3.13, 6.25, 12.5, 25, 50 and 100 µM	[21]
	MCF10DCIS.com	Induces apoptosis	↓ TNF-α induced cell migration and invasion, no effect on IκBα expression and NF-κB p65 phosphorylation, ↓ Gli1, ↓ MMP-9	Daidzein—0, 5, 10, 30 and 50 µM and Equol—10 μM	[22]
	MCF-7	Induces apoptosis	↓ MCF-7 viability, ↑ %age of apoptotic cells, ↑ % age cells sub-G₁ phase, ↓ % age cells in G₀/G₁, S and G₂/M phase, ↑ p53, ↑ p21, ↑ PARP cleavage, ↑ α-fodrin proteolysis, ↑ pro-caspase-7 and pro-caspase-9 cleavage, ↓ Bcl-2, ↑ cytochrome-c release to the cytosol, ↓ Bcl-2: Bax ratio, ↑ tamoxifen’s anti-tumor activity	Equol—0, 25, 50 and 100 μM and 4-OHT 0, 0.01, 0.1, 1.0, 10.0 μM	[23]
	MCF-7 and MDA-MB-453	Induces apoptosis	↓ cell proliferation of cancer cells, ↑ cell cycle arrest in the G₁ and G₂/M phases, ↑ %age cells in sub-G₀ phase, ↓ cyclin D, ↓ CDK2, ↓ CDK4, No Change in the expression of CDK6 and cyclin E, ↓ CDK 1, ↑ p21Cip1 and ↑ p57Kip2, No change in p27Kip1	Daidzein—1–100 μM	[24]
	MCF-7/MDA MB-231	Induces apoptosis	↓ viability of MCF-7 and MDA MB-231 cell lines, no significant growth inhibition was observed in MCF-10A cells, ↑ no of rounded cells due to shrinkage and condensation of cytoplasm, ↑ apoptotic cells, ↑ tunnel +live cells, ↑ ROS, ↓ ∆ψm, ↓ Bcl-xL, ↑ BAX, ↑ Caspase 3/7/9, ↑ cleaved PARP, ↓ PI3K, ↓ p-Akt, ↓ p-mTOR, ↑ affectivity of Centchroman	Centchroman—1–30 µM and Daidzein 10–200 µM	[25]
	MCF-7 and MDA-MB-231	Induces apoptosis	↑ MRP2, ↓ MRP1, ↓ ABCC2 and ABCC1 mRNA	Daidzein—0.05, 0.5 and 5 µM, R-equol and S-equol—0.1, 1 and 10 µM	[26]
	MCF-7	Enhances apoptosis-inducing activity of genistein	↑ cytotoxicity of genistein, ↑ G₂/M phase cells, ↓ G₁/S blockade and G₂/M progression ↑ sub-G₀/G₁ population ↑ apoptosis rate, ↑ Bax/Bcl-xL expression ratio, No change in activities of Akt and mTOR, ↑ c-PARP	Genistein—0–100 µM, Equol—0–100 µM	[27]
	MDA-MB-435 (ER)	Induces apoptosis	↑ eIF4GI, ↑ c-Myc, ↑ Cyclin D ↑Bcl-XL ↑ p120 catenin	(R, S) Equol—25 μM	[28]
	MDA-MB-231	Inhibit metastasis	↓ invasive capacity, ↓ MMP-2, No Change on n the expression levels of MMP- 9, TIMP-1 or TIMP-2	Daidzein, R—and S-Equol—0, 2.5, 10, 50 µM	[29]
	MCF-7	Induces apoptosis	↑ ROS, ↓ Bcl-2, ↑ Bax, ↑ release of cytochrome C from the mitochondria into the cytosol, ↑ caspase-9, ↑ caspase-7	Daidzein—25–100 µM	[30]
	MCF-7	--	↑ antiproliferative effects, ↑ pS2 mRNA	Daidzein and (±)-equol 0.001 to 50 µM	[31]
Lung	A594 and 95D	Induces apoptosis	↓ proliferation and colony formation property of cancer cells ↓ IL-6, ↓IL-8, ↓ p65-NFκB expression and activation, ↓ level of p65-NFκB upregulation induced by C/EBPβ	Daidzein—0, 5, 10, and 25 μM	[32]
Lung	A549, HepG-2	Induces apoptosis	↑ ROS, ↓ mitochondrial membrane potential, ↑ apoptosis rate, ↑ cell cycle arrest at the G₂/M phase, ↓ Bcl-2, ↓ Bcl-x and ↓ Baid proteins, ↑ Bim protein	Daidzein—IC₅₀ value of 59.7 µM	[33]
Gastric	MGC-803	Induces apoptosis	↓ viability of MGC-803 cells, ↑ G₀/G₁ cell cycle arrest, ↓ CDK2/4, ↓ Cyclin D1/Cyclin E1 ↑ P21WAF1, ↑ apoptosis frequency, ↑ cleaved PARP, ↑ caspase-3. ↑ P-Akt (Ser473 and Thr308)	Equol—5, 10, 20, 40, or 80 μM	[34]
Gastric	BGC-823	Induces apoptosis	↓ growth and proliferation of gastric carcinoma cells, ↓ mitochondrial transmembrane potential ↑ cleaved PARP, ↑ cleaved caspase-9, ↑ cleaved caspase-3, ↑ Bax, ↓ Bcl-2, ↓ Bcl-2/Bax	Daidzein—0, 20, 40, and 80 µM	[35]
Hepatocellular	SMMC-7721 and HepG2	Induces apoptosis	↓ proliferation, migration and invasion of cancer cells, ↓ concentrations of pyruvate, glutamate and glucose, ↓ activities of hexokinase, phosphofructokinase and pyruvate kinase, ↓ pyruvate kinase M2, ↑ levels of glycerophosphocholine, ethanolamine, taurine, fumarate, leucine, acetate, ↓ levels of pyruvate, glutamate, glutamine, adenosine monophosphate, creatine, glycine	(−)—5-hydroxy Equol—0, 10, 20, 30, 40 and 50 µM	[36]
	SMMC-7721	Induces apoptosis	↓ proliferation of SMMC-7721 cells, ↑ apoptosis frequency, ↑ S-phase cell cycle arrest, ↑ p21, ↓ cyclin A2; No change in expression of cyclin D1 and H2AX, ↑ caspase-9, ↑ caspase-3, ↑ c-PARP, ↑ Bax ↓ Bcl-2, ↑ caspase-8, ↑ caspase-12, ↑ Chop, ↑ Bip	(±)—Equol, R-(+)-Equol, and S-(–)-Equol—0, 5, 10, 20, 50, and 100 µM	[37]
	SK-HEP-1	Induces apoptosis	↓ cell proliferation of cancer cells, ↑ Prdx-3, ↑ Bak, ↓ Bcl-2, ↓ Bcl-xL, ↑ release of mitochondrial cytochrome c to cytosol, ↑ APAF-1, ↑ caspase 9, ↑ caspase 3	Daidzein—0, 200, 400 and 600 µM	[38]
Pancreatic	MiaPaCa-2 and PANC-1	Induces apoptosis	↓ growth and proliferation of pancreatic cancer cells, inhibitory effects on both ER positive and negative pancreatic cancer cells	Daidzein—0.1, 1, 10, 25, 50, 75 and 100 µmol/L	[39]
Colorectal	SW620	Anti-proliferative effects	↓ p-ERK/ERK, ↓ p-AKT/AKT	Chrysin IC₅₀ values 70 µM and Daidzein IC₅₀ values 23.5 µM	[40]
Colorectal	HCT-15	Induces apoptosis	Racemic equol ↓ proliferation of HCT-15 cells, whereas(S) equol had no effect on the proliferation of HCT-15 cells. Racemic equol ↓ ERβ and ↓ Nrf2, while (R) equol ↓ Nrf2	Racemic equol and equol enantiomers—0, 0. 5, 1, 5 and 10 μM	[41]
Bladder	RT112, RT4 and SW780	Induces apoptosis	↓ cell viability, Impaired colony formation, ↑ G1/S cell cycle arrest, ↑ apoptosis frequency, ↓ FGFR3 signaling pathway, ↓ p-FGFR3, ↓ p-Akt, p-ERK	Daidzein—0, 0.5, 1, 2.5, 5, 7.5, 10, 50 and 100 μM	[42]
Prostate	DU145, LNCaP and PC3	Induces apoptosis	↑ cytotoxic activity, ↑ ERβ binding activity, ↑ ERβ gene expression, ↓ cMYC, ↓ Cyclin D1 genes, ↑ caspase 3 and 9, No change in uterotropic and anti-androgenic activities	Novel daidzein molecules—1, 5, 10, 50, 100, 200, 300, 400, 500 µM	[43]
	LNCaP, DU145 and PC3	Induces apoptosis	↑ cell cycle arrest in the G₂/M phase↓ Cyclin B1 ↓ CDK1, ↑ p21 and p27, ↑ apoptosis rate, ↑ FasL ↑ Bim. ↑ FOXO3a, ↓ p-FOXO3a, ↑ nuclear stability of FOXO3a, ↓ MDM2	S-Equol—0, 0.5, 1, 5, 10 μM	[44]
	DU145	Induces apoptosis	↓ cell migration and invasion, ↓ MMP-, ↓ u-PA, ↓ secreted MMP-2 and MMP-9, ↑ SOD, ↑ Nrf2, ↑ PTEN	(±) Equol 5, 10, 50 µM, Daidzein and Genistein—0.5, 1 and 5 µM	[45]
	PC3, DU145 cells	Induces apoptosis	↓ MMP-2, ↓ MMP-9, ↑ ERγ, No change in Erβ	Equol—0, 0.5, 1, 5, 10 μM	[46]
Choriocarcinoma	JAR and JEG-3	Induces apoptosis	↓ cell viability, ↑ early and late apoptotic cells, ↑ apoptosis frequency, ↑ caspase-9, ↑ caspase-3, ↑ c-PARP, ↓ Bcl-2/Bax	Daidzein—0, 25, 50 or 100 µM	[29]
Cervix	BEL-7402, HeLa,	Induces apoptosis	↑ ROS, ↓ mitochondrial membrane potential, ↑ apoptosis rate, ↑ cell cycle arrest at the G₂/M phase, ↓ Bcl-2, ↓ Bcl-x and ↓ Baid proteins, ↑ Bim protein	Daidzein—IC₅₀ value of 59.7 µM	[47]
Ovarian	caov-3, OVAcAR-3, SKOV3 and A2780	Induces apoptosis	↑ antiproliferative effects on SKVO3 cells, SKOV3 cancer cells became rounder, shrunken and detached from the substratum, ↑ apoptotic cells, ↑ release of cytochrome c into the cytoplasm, ↑ cytosolic levels of cyt c, ↑ Bax, ↑ cleaved caspase-3 and -9, ↑ cleaved PARP, ↑ G₂ phase cells leading to G₂/M cell cycle phase arrest, ↓ pcdc25c (Ser216), ↓ cdc25c, ↓ pcdc2 (Tyr15), ↓ cdc2, ↓ cyclin B1, ↑ p21, ↓ migratory capability of cancer cells, ↓ MMP-9, ↓ MMP-2, ↓ p-MEK, ↓ p-ERK	Daidzein—0, 10, 20 and 40 µM	[48]