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] |
| 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] |
| 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] |
| 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] |
| 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] |
| 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] |