Why Do Dietary Flavonoids Have a Promising Effect as Enhancers of Anthracyclines? Hydroxyl Substituents, Bioavailability and Biological Activity
Abstract
:1. Introduction
2. Anthracyclines—Toxicity and Mechanism of Action
3. Flavonoids—Structure, Bioavailability and Molecular Activity
3.1. General Structure of Flavonoids
3.2. Absorption and Metabolism of Flavonoids Determine In Vivo Activity
3.3. Bioavailability of Flavonoids Conditioned by Physicochemical Parameters
4. Anthracycline and Flavonoids Crosstalk
4.1. Glutathione Depletion and Oxidative Stress
4.2. Flavonoids As Inhibitors on Nrf-2/ARE Pathway
4.3. Flavonoids As Agonist and Antagonist of Nuclear Receptors
5. Modulatory Effect of Flavonoids on the Activity of Multidrug Response Proteins
5.1. Modulation Effect of Flavonoids on Cytochrome P450 3A4 (CYP3A4) Activity
5.2. Flavonoids Interactions with Organic Anion-Transporting Polypeptide (OATP)
5.3. Role of Flavonoids in ABC Transporters Activity in Cancer Cells
6. Genotoxicity vs. Genoprotection in Anthracycline-Treated Cells
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Appendix A
Cell Line | CHRY | API | KAE | QUE | MIR | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
IC50 | Assay | Ref | IC50 | Assay | Ref | IC50 | Assay | Ref | IC50 | Assay | Ref | IC50 | Assay | Ref | |
MDA-MB-468 | 5.84 ± 0.67 μM | MTT, 72 h | [235] | 8.9 μg/mL | 72 h | [237] | 23 μg/mL | 72 h MTT | [238] | 18.1 + 1.6 μM | TIA | [239] | |||
MDA-MB-231 | 47.0 + 2.9 μM | TIA | [239] | >100 μM | MTT, 24 h | [240] | 114.75 µM | MTT, 72 h | [241] | ||||||
40 (35–45) μM | TBE + CTG 72 h | [242] | 75.12 ± 1.85 μM | MTT. 24 h | [243] | 34 μg/mL | MTT, T72 h | [238] | >200 μM | MTT, 24 h | [243] | 30.29 ± 1.87 μM | MTT, 24 h | [243] | |
>200 | MTT, 24 h | [243] | 101 (82–124) μM | TBE + CTG 72 h | [242] | >200 μM | TBE + CTG 72 h | [242] | |||||||
38 μM | TBE + CTG 72 h | [242] | |||||||||||||
MCF-7 | 4.20 ± 1.70 μM | MTT, 72 h | [235] | 37.2 ± 3.7 μM | WST-1, 48 h | [244] | 25 (16–40) μM | TBE + CTG 72 h | [242] | 37 μM | MTT, 24 h | [240] | >200 μM | TBE + CTG 72 h | [242] |
34 (28–40) μM | TBE + CTG 72 h | [242] | 7.8 μg/mL | 72 h | [237] | 102 (62–161) μM | TBE + CTG 72 h | [242] | |||||||
25.6 ± 1.2 µM | MTT, 72 h | [245] | >80 µM | CQ, 72 h | [246] | ||||||||||
13.7 ± 0.6 µM | MTT, 72 h | [245] | |||||||||||||
HeLa | 86.51 ± 2.9 | MTT, 48 h | [247] | 10 µM | MTT, 48 h | [248] | 50 µM | MTT, 48 h | [249] | 35.5 ± 1.1 µM | MTT, 72 h | [250] | 9.06 µM | MTT, 24 h | [251] |
41.0 ± 4.5 | WST-1.48 h | [244] | |||||||||||||
74.71 ± 3.6 µg/mL | MTT, 48 h. | [252] | |||||||||||||
HepG2 | 10.69 ± 0.94 μM | MTT, 72 h | [235] | 57.86 ± 2.9 µg/mL | MTT, 48 h | [252] | 30.92 μM | RFR, 24 h | [253] | 87 μM | TBE, 18 h | [254] | 87.84 μM | CCK-8, 72 h | [255] |
37.4 ± 3.8 | WST-1, 48 h | [244] | |||||||||||||
HT-29 | 126.5 ± 6.3 | SG, 72 h | [256] | 130.6 ± 6.8 | SG, 72 h | [256] | 136.9 ± 7.4 | SG, 72 h | [256] | 85.59 ± 8.6 μM | SG, 72 h | [256] | 47.6 ± 2.3 µM | SG, 72 h | [256] |
Caco-2 | 4.84 0.19 µM | MTT, 72 h | [235] | 115.4 ± 10.3 μM | SG 72 h | [256] | 163.2 ± 1.6 μM | SG, 72 h | [256] | 96.3 ± 6.7 μM | SG 72 h | [256] | 88.4 ± 3.4 µM. | SG, 72 h | [256] |
115.6 ± 2.1 μM | SG, 72 h | [256] | |||||||||||||
HCT-116 | 4.07 ± 0.29 µM | MTT, 72 h | [235] | 34.4 ± 3.6 µM | WST-1, 48 h | [244] | 7.2 μM | WST-8, 72 h | [257] | 40 µM | MTT, 48 h | [258] | No effect | MTT, 72 h | [241] |
LNCaP | 75 µM | MTT, 48 h | [258] | 25 µM | DC, 72 h | [259] | 53.8 μM | xC, 24 h | [260] | ||||||
56.81 µM | CQ, 72 h | [246] | 28:8 ± 1:5 μM | MTT, 48 h | [261] | 19.44 µM | CQ, 72 h | [246] | |||||||
20 µM | DC, 72 h | [259] | 33.3 μM | xC, 24 h | [260] | ||||||||||
PC-3 | 50 µM | DC, 72 h | [259] | 52.24 µM | CQ 72 h | [246] | 14.5 μM | xC 24 h | [260] | 47.6 μM | CCK-8, 48 h | [262] | |||
>20 μM | MTT, 48 h | [263] | 58:3 ± 3:5 μM | MTT, 48 h | [261] | 50 µM | DC, 72 h | [259] | |||||||
>100 µM | CQ, 72 h | [246] | 38.8 ± 3.9 | WST-1, 48 h | [244] | 41.98 µM | CQ, 72 h | [246] | 33.41 µM | CQ, 72 h | [246] | ||||
A549 | 4.64 ± 1.36 µM | MTT, 72 h | [235] | 93.7 ± 3.7 μM | MTT, 4 h | [264] | 72 μM | MTT, 24 h | [265] | 8.65 µg/mL | 24 h, MTT | [266] | 154.3 ± 4.6 | CCK-8, 48 h | [267] |
49.2 ± 0.6 µM | WST-8, 48 h | [268] | 35.4 ± 3.7 | WST-1, 48 h | [244] |
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CHRY | API | KAE | QUE | MIR | DOX | ||
---|---|---|---|---|---|---|---|
Physicochemical Properties 1 | Molecular Weight | 254.24 | 270.24 | 286.24 | 302.24 | 318.24 | 543.52 |
Volume | 206.92 | 216.03 | 224.05 | 232.07 | 240.08 | ||
Aromatic heavy atoms | 12 | 16 | 16 | 16 | 16 | 12 | |
H-bond acceptors | 4 | 5 | 6 | 7 | 8 | 7 | |
H-bond donors | 2 | 3 | 4 | 5 | 6 | 12 | |
TPSA | 70.67 | 90.9 | 111.13 | 131.36 | 151.59 | 206.08 | |
SILICOS-IT Log P 2 | 3.02 | 2.52 | 2.03 | 1.54 | 1.06 | 1.17 | |
ESOL Log S | −4.19 | −3.94 | −3.31 | −3.16 | −3.01 | 132.66 | |
Molar Refractivity | 71.97 | 73.99 | 76.01 | 78.03 | 80.06 | 131.52 | |
Pharmacokinetics 1 | CYP1A2 | + | + | + | + | + | − |
CYP2C19 | − | − | − | − | − | − | |
CYP2C9 | + | − | − | − | − | − | |
CYP2D6 | − | + | + | + | + | − | |
CYP3A4 | + | + | + | + | + | − | |
DFT electrochemical parameters 3,4 | HOMO [eV] | −6.43 | −6.24 | −5.78 | −5.65 | −5.71 | −5.32 |
LUMO [eV] | −2.04 | −1.88 | −1.97 | −1.97 | −2.06 | −4.09 | |
HOMO-LUMO energy gap [eV] | 4.39 | 4.36 | 3.81 | 3.68 | 3.65 | 1.23 | |
Dipole moment | 3.84 | 2.47 | 5.47 | 4.23 | 6.78 | 7.77 | |
Electron affinity | 4.24 | 4.06 | 3.87 | 3.81 | 3.88 | 6.80 |
Compound | Concentration | Cell Line | Cell Type | Effect | Ref |
---|---|---|---|---|---|
Chrysin | 10–20 µM | BEL-7402/ADM cells | Hepatocellular carcinoma | ↓ mRNA and protein expression of Nrf2, HO-1, MRP5, and aldo-keto reductase family 1 member B10 (AKR1B10) | [137] |
Chrysin [nanostructural lipid carriers] | 5–50 µM | MCF-7 | Breast cancer | ↓mRNA and protein expression of Nrf2; NQO1, HO1 i MRP1 | [141] |
Chrysin | 10–60 µM | T98, U251, U87 | human glioblastomas | ↓ Nrf2, NQO-1, HO-1 (Keap1-independent); ↓ ERK signaling | [142] |
Apigenin | 10 μM | BEL-7402/ADM | Hepatocellular carcinoma | inhibiting miR-101/Nrf2 pathway | [143] |
Kaempferol | 25 μM | A549, NCIH460 | NSCLC | ↓ mRNA and protein expression of Nrf2; ↓ AKR1C1, NQO1, HO1 i GS; ↑ ROS | [144] |
25–50 μM | PANC-1, PaCa-2 | pancreatic cancer | ROS-dependent suppression Akt/mTOR signaling; ↓ Keap; Nrf2 (ambiguous impact) | [145] | |
Quercetin | 50 μM | human xenograft acute myeloid leukemia (AML) models, and in vitro using leukemia cell lines | ↓ Nnf2 nuclear localization; ↓ pNrf2 ↓ HDAC4; | [146] |
Cell Internalization of Rhodamine-123 in MCF-7/ADR 1 Cells Overexpressing P-gp | Ref | Human CYP3A4 Microsomes Expressed in Baculovirus 2-Insect Cell, Lineweaver–Burk Plot Analysis | Ref | Residual Activity Compared to Control (6β-Hydroxylation of Testosterone-Marker Reaction of CYP3A4 Activity) | Ref | ||
---|---|---|---|---|---|---|---|
Flavonols | Myricetin | 7.8 | [185] | 44.5 | [186] | 133 ± 35 | [187] |
Quercetin | 1.97 | [182] | 22.1 | [186] | 126 ± 10 | [187] | |
Kaempferol | 8.6 | [182] | 8.8 | [186] | 101 ± 14 | [187] | |
Flavones | Apigenin | 1.8 | [182] | 0.4 | [186] | 24 ± 3 | [187] |
Chrysin | nd | 0.9 | [186] | 17 ± 3 | [187] |
Binging Constants (K[M−]]) | Methods | DNA Model | Measurement Conditions | References | |
---|---|---|---|---|---|
CHRYSIN | 1.21 × 105 | Abs | d(CCAATTGG)2 | room temperature; absorption: 200 to 800 nm; fluorescence: Ex 326 nm, Em spectra 320 to 650 nm, | [227] |
9.07 × 103 | Fluo | ||||
9.03 × 105 | Abs | Ct-DNA | |||
3.03 × 105 | Fluo | ||||
APIGENIN | 7.10 × 104 | FT-IR & Abs | Ct-DNA | FT-IR: sharp DNA band at 968 cm−1 as internal reference, obtained difference spectra [(DNA solution + ligand)-(DNA solution)]; Abs: of DNA at 260 nm, wavelength range of 245–445 upon titration of dsDNA | [225] |
9.12 × 104 | Abs | dsDNA | [226] | ||
0.73 × 104 | Abs | Ct-DNA | [140] | ||
QUERCETIN | 17.54 × 105 | Fluo, 300 K | Ct-DNA | fluorescence: Ex 220–660 nm 57; Em 240–680 nm | [229] |
8.97 × 105 | Fluo, 310 K | ||||
4.80 × 105 | Fluo, 320 K | ||||
18.0 × 10 4 | Abs | Ct-DNA | [140] | ||
KAEMPFEROL | 18.0 × 104 | Abs | Ct-DNA | measurement of absorption between 200 nm and 500 nm | [140] |
MYRICETIN | 8.63 × 104 | Abs | Ct-DNA |
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Golonko, A.; Olichwier, A.J.; Swislocka, R.; Szczerbinski, L.; Lewandowski, W. Why Do Dietary Flavonoids Have a Promising Effect as Enhancers of Anthracyclines? Hydroxyl Substituents, Bioavailability and Biological Activity. Int. J. Mol. Sci. 2023, 24, 391. https://doi.org/10.3390/ijms24010391
Golonko A, Olichwier AJ, Swislocka R, Szczerbinski L, Lewandowski W. Why Do Dietary Flavonoids Have a Promising Effect as Enhancers of Anthracyclines? Hydroxyl Substituents, Bioavailability and Biological Activity. International Journal of Molecular Sciences. 2023; 24(1):391. https://doi.org/10.3390/ijms24010391
Chicago/Turabian StyleGolonko, Aleksandra, Adam Jan Olichwier, Renata Swislocka, Lukasz Szczerbinski, and Włodzimierz Lewandowski. 2023. "Why Do Dietary Flavonoids Have a Promising Effect as Enhancers of Anthracyclines? Hydroxyl Substituents, Bioavailability and Biological Activity" International Journal of Molecular Sciences 24, no. 1: 391. https://doi.org/10.3390/ijms24010391