Biphasic Dose-Response Induced by Phytochemicals: Experimental Evidence
Abstract
:1. Introduction
2. Phytoestrogens
3. Resveratrol
4. Other Phytochemicals
5. Comments
Author Contributions
Funding
Conflicts of Interest
Abbreviations
2-AAF | 2-Acetylaminofluorene |
4NQO | 4-nitroquinoline-N-oxide |
6-OHDA | 6-Hydroxydopamine |
AChE | Acetylcholinesterase |
AFB1 | Aflatoxin B1 |
AKT | Serine/threonine protein kinase |
ALP | Alkaline phosphatase |
apoM | Apolipoprotein M |
b.w. | Bodyweight |
B16-F10 | Murine melanoma cell line |
Bcl-2 | B-cell lymphoma 2 |
BER | Berberine |
BMSCs | Bone marrow-derived mesenchymal stem cells |
C2C12 | Mouse myoblast cell line |
CA | Caffeic acid |
CaCo-2 | Human colon cancer cell line |
CD203c | Basophil-specific ectoenzyme E-NPP3 |
CD63 | Tetraspan transmembrane protein family |
CES | Carboxylesterase |
CIN | Chromosomal instability |
CLS | Chronologic life span |
CYN | Cynarin |
CYP | Cytochrome P450 |
CYP1A2 | Cytochrome P450 1A2 |
DAI | Daidzein |
ER | Estrogen receptor |
ERK | Extracellular signal-regulated kinase protein-serine/threonine kinase |
fMLP | Bacterial formyl peptide N-formylmethionine-leucine-phenylalanine |
FSF-1 | Human skin fibroblasts |
GEN | Genistein |
GIR | Genotoxic inhibition rate |
GPx | Glutathione peroxidase |
GSH | Reduced glutathione |
GSSG | Oxidized glutathione |
GST | Glutathione S-transferase |
HCT-116 | Colon carcinoma cell lines |
HepG2 | Human liver cancer cell line |
HHL-5 | Human normal liver cell line |
HO-1 | Heme oxygenase-1 |
Hsp70 | 70 kDa heat shock protein |
HT-29 | Colon carcinoma cell lines |
hTERT-MSC | Human normal telomerase-immortalized mesenchymal stem cells |
HUVEC | Human umbilical vein endothelial cell line |
ISL | Isoliquiritigenin |
Jurkat T-CLL | Jurkat T-cell lymphocyte leukemia cells |
K+ -p-NPPase activity | K+ -p- nitrophenylphosphatase |
K562 | Immortalized cell line derived from human leukemia |
KS483 | Murine osteoprogenitor cell line |
LC3-II | Microtubule-associated protein 2 light chain 3 |
LNCaP | Androgen-sensitive human prostate adenocarcinoma cell line |
LoVo | Human colon adenocarcinoma cell line |
LS-174 | Human colon cancer cell line |
LVDP | Left ventricular developed pressure |
MAPK | Mitogen-activated protein kinase |
MCF-7 | Human breast adenocarcinoma cell line |
MDA-MB-231, MDA-MB-468, MCF-7MCF-7 | Human breast carcinoma cell lines |
MeIQ | 2-amino-3,4-dimethylimidazo [4,5-f]quinoline |
MG-63 | Human osteoblast-like cells |
MMPs | matrix metalloproteinases |
MN | Markers micronuclei |
MSCs | Mesenchymal stem cell line |
NHDF | Neonatal normal human dermal fibroblasts |
NHEK | Neonatal normal human epidermal keratinocytes |
NK | Human natural killer cells |
NPB | Nucleoplasmic bridge |
NPCs | Neural progenitor cells; ODC - ornithine decarboxylase |
OGD | Oxygen-glucose deprivation |
pBMEC | Primary bovine mammary epithelial cells |
PC-12 | Phaeochromocytoma cell line |
PC-3 | Human prostatic carcinoma cell line |
PCNA | Proliferating cell nuclear antigen |
PGE2 | Prostaglandin E2 |
PI3K | Phosphoinositide 3-kinase |
PKC | Protein kinase C |
PMA | Phorbol myristate acetate |
PPARγ | Peroxisome proliferator-activated receptor γ |
PTS | Panaxatriol saponins |
PVC | Pericytes |
QER | Quercetin |
RA | Rosmarinic acid |
RAW 264.7 | Murine macrophage cell line |
RES | Resveratrol |
ROS | Reactive oxygen species |
RWPE-1 | Nontumorigenic human prostate epithelial cells |
SCC-25 | Oral squamous carcinoma cell line |
SFN | Sulforaphane |
SKN-1 | Transcription factor skinhead-1 |
SOX2 | Transcription factor (sex determining region Y-box 2 |
T24 | Bladder cancer cell line |
T-47D, T | Human breast cancer cell lines |
TIMP-2 | Tissue inhibitor of metalloproteinase-2 |
TRAMP-FVB | Transgenic adenocarcinoma of mouse prostate model |
UtLM | Human uterine leiomyoma |
UtSMCs | Uterine smooth muscle cells |
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Compound * | Model | Concentration | Effects | Mechanism | Refs |
---|---|---|---|---|---|
Effects Linked to Estrogenic Activity | |||||
Artelastin Artelastocarpin Artelastochromen Carpelastofuran isolated from Artocarpus elasticus | MCF-7 | 0.02–2.90 μM | ↑proliferation, DNA synthesis | [38,39] | |
>3.12 μM | ↓proliferation | ||||
25 μM | ↓DNA synthesis | ||||
Biochanin A | MCF-7 | ~4–35 μM | ↑proliferation | [37] | |
~106–352 μM | ↓proliferation | ||||
~18 μM | ↑DNA synthesis | ||||
~70 μM | ↓DNA synthesis | ||||
T-47D | ~4 μM | ↑proliferation | ↓p53 | [24] | |
~70 μM | ↓proliferation | ↑p53 | |||
Breviflavone B isolated from Epimedium brevicornum | MCF-7 | 450 nM | ↑proliferation | [40] | |
2.2–6.6 μM | ↓proliferation | ↓ERα | |||
Daidzein | T-47D | ~1–79 μM | ↑proliferation | ↓p53 | [24] |
~157 μM | ↓proliferation | ↑p53 | |||
MCF-7 | ~1 μM | ↑proliferation | [25] | ||
>10 μM | ↓proliferation | ||||
LoVo | 0.1, 1.0 μM | ↑proliferation | [26] | ||
10–100 μM | ↓proliferation | G0/G1 arrest | |||
↑caspase-3 | |||||
KS483, mouse bone marrow cells | <20 μM | ↑osteogenesis ↓adipogenesis | PPARs transactivation | [27] | |
>30 μM | ↓osteogenesis ↑adipogenesis | ||||
Enterodiol Enterolactone | MG-63 | ~33 μM | ↑viability | ↑osteonectin ↑collagen I | [43] |
~33–333 μM | ↑ALP activity | ||||
>333 μM | ↓viability | ↓osteonectin ↓collagen I | |||
~3–33 mM | ↓ALP activity | ||||
Genistein | MCF-7 | <1 μM | ↑proliferation | ↑ER transcription | [11,12,13,14,15,17,18,19] |
>10 μM | ↓proliferation | ||||
PC-3 | 500–1000 nM | ↑proliferation, | ↑MMP-9 activity | [20] | |
↑osteopontin | |||||
50,000 nM | ↓proliferation | ↓MMP-9 activity | |||
RWPE-1 | 1.5–12.5 μM | ↑proliferation | ↑ERK1/2 activity | [21] | |
50 and 100 μM | ↓proliferation | ||||
UtLM | ~4 μM | ↑proliferation | [22] | ||
↑PCNA, ↑cells in S phase | |||||
>37 μM | ↓proliferation ↑apoptosis | ||||
KS483, mouse bone marrow cells | 0.1–10.0 μM | ↑osteogenesis ↑ALP activity | [23] | ||
↑nodule formation and calcium deposition | |||||
>25 μM | ↓osteogenesis ↓ALP activity | ||||
↓nodule formation and calcium deposition | |||||
KS483, mouse bone marrow cells | 0.1–1.0 μM | ↓adipocytes number | [23] | ||
10–50 μM | ↓adipocytes number | ||||
Glabrene isolated from Glycyrrhiza glabra | T47-D, MCF-7 | 100 nM–10 μM | ↑proliferation | [42] | |
>15 μM | ↓proliferation | ||||
Glabridin isolated from Glycyrrhiza glabra | T-46D | 0.1–10 μM | ↑proliferation | [41] | |
>15 μM | ↓proliferation | ||||
Isoliquiritigenin synthesized by authors | MCF-7 | <1 μM | ↑proliferation | [44] | |
10 μM | ↓proliferation | ||||
Kaempherol | MCF-7 | <1 μM | ↑proliferation | [46] | |
>1 μM | ↓proliferation | ||||
Quercetin | MCF-7 | <1 μM | ↑proliferation | [17] | |
>10 μM | ↓proliferation | ||||
HCT-116 | 1–30 μM | ↑proliferation | [28] | ||
40–100 μM | ↓proliferation | ||||
HT-29 | 1–67 μM | ↑proliferation | |||
80–100 μM | ↓proliferation | ||||
SCC-25 | 1–10 μM | ↑proliferation | [29] | ||
>100 μM | ↓proliferation | ||||
Activity not Linked to Estrogenic Properties | |||||
Isoliquiritigenin | HUVEC/PMA | <10 μM | ↑TIMP-2 | ↓JNK, p38 MAPK pathway | [45] |
25 μM | ↓TIMP-2 | ||||
Quercetin | RAW 264.7 | 10–100 nM | ↑PGE2 | [30] | |
10–100 μM | ↓PGE2 | ||||
basophils/fMLP | ~0.03–0.33 μM | ↑CD63, CD203c | [32] | ||
~3–33 μM | ↓CD63, CD203c | ||||
basophils/fMLP | 0.03–0.3 μM | ↑histamine | PI3K involvement | [33] | |
33 μM | ↓histamine | ||||
Caenorhabditis elegans | 100–200 μM | ↑lifespan | ↑hsp | [34] | |
250 μM | ↓lifespan | ||||
Salmonella typhimurium/AFB1 | 0.006–0.01 mM | ↓mutagenicity | [35] | ||
0.06–0.12 mM | ↑mutagenicity | ||||
Salmonella typhimurium/MeIQ | 0.1, 1 μM | ↑mutagenicity, CYP1A2 activity | [36] | ||
50, 100 μM | ↓mutagenicity, CYP1A2 activity |
Model | Concentration | Effects | Mechanism | Refs |
---|---|---|---|---|
NHEK | <50 μM | ↑viability | ↑CAT, Nrf2, KEAP1, NQO1, GCLC, GSR, G6PD, FOXO3, SIRT1, DAPK 1 (5–100 µM) | [48] |
500 μM | ↓viability | ↓CAT, Nrf2, KEAP1, NQO1, GCLC, GSR, G6PD, FOXO3, SIRT1, DAPK1 150 µM | ||
NHDF | 1–300 μM | ↑viability | ||
500 μM | ↓viability | |||
HepG2 | 1–100 μM | ↑viability | ||
500 μM | ↓viability | |||
NPCs | 1, 10, 20 μM | ↑proliferation | ↑ERK1/2, p38, p-CREB, Bcl-2, TrkA, synaptophysin, PSA-NCAM | [49] |
50, 100 μM | ↓proliferation | ↓p-ERK1/2, p-p38 MAPK | ||
↑caspase-3 | ||||
HT-29 | 1–10 μM | ↑proliferation | [50] | |
50, 100 μM | ↓proliferation | ↑NADPH oxidase activity, ↑ɣH2AX, SIRT6 | ||
Bovine spermatozoa | 1–50 μM | ↑viability | [51] | |
↓superoxide anion production | ||||
100, 1000 μM | ↓viability | |||
100, 200 μM | ↑superoxide anion production | |||
LNCaP | 5 μM, 10 μM | ↑DNA synthesis | ↓p21cip1, p27kip1 | [52] |
↑Cdk2 activity | ||||
↑cyclins A, E | ||||
>15 μM | ↓DNA synthesis | |||
Rat ovarian | 10 μM | ↑DNA synthesis | [53] | |
granulosa cells | 30,50 μM | ↓DNA synthesis | ||
Normal colon epithelial cells | 0.1–1 μM | ↓chromosomal instability, ↑viability | ↑SAC | [54] |
100 μM | ↑chromosomal instability, ↓viability | ↓SAC | ||
C12C12 | 10 μM | ↑cell motility | [55] | |
40–60 μM | ↓cell motility | ↓miosin Tpe1 and total ATPase activity | ||
HepG2 | 1, 10 μM | ↑apoM, | [56] | |
100 μM | ↓apoM | |||
hMSCs | 0.1 μM | ↓cellular senescence | ↑Sirtuin1 | [57] |
5, 10 μM | ↑cellular senescence | ↓Sirtuin1, Sirtuin2, Birc4, Birc5 | ||
↑Cdk2 | ||||
HepG2/4NQO | 10, 25, 50 μM | ↓genotoxicity | [58] | |
100, 250 μM | ↑genotoxicity | |||
NK | 1.56, 3.13 μM | ↑cytotoxicity | ↑NKG2D, NKG2D | [59] |
↑IFN-γ, IFN-γ | ||||
25, 50 μM | ↓cytotoxicity | |||
HUVEC | 1 μM | ↓ROS | ↑Bcl-2, c-myc, ODC | [60] |
↑viability, DNA synthesis | ↑PKC activity | |||
10, 50 μM | ↑ROS | ↓Bcl-2, c-myc, ODC | ||
↓viability, DNA synthesis | ↓PKC activity | |||
Rats | 2.5 mg/kg | ↑aortic flow, LVDP, ↓infarct size | ↓cardiomyocyte apoptosis | [61] |
25 mg/kg | ↓aortic flow, LVDP, ↑infarct size | ↑cardiomyocyte apoptosis | ||
100 mg/kg | no heart function | ↑cardiomyocyte apoptosis |
Compound * | Model | Concentration | Effect | Mechanism | Refs |
---|---|---|---|---|---|
Arctigenin | K-562 | ~27, 54 μM | ↑Mcl-1mRNA | [85] | |
~107 μM | ↓Mcl-1mRNA | ||||
Berberine | B16-F10, | 1.25–5.00 μM | ↑proliferation | ↑MAPK/ERK1/2 ↑PI3K/AKT | [70] |
MDA-MB-231, | 10–80 μM | ↓proliferation | |||
MDA-MB-468, | |||||
MCF-7, LS-174 | |||||
PC-12 | 0.1–1.0 μM | ↑viability | ↑PI3K/AKT/Bcl-2 | [71] | |
2–64 μM | ↓viability | ||||
Caffeic acid | male F344 rats | 0.14% | ↓proliferation | ↓epithelial cells, S-phase cells | [90] |
0.40, 1.64% | ↑proliferation | ↑epithelial cells, ↓S-phase cells in forestomach | |||
(+) Catechin, rutin | Salmonella typhimurium/2-AAF | 0.01–0.60 mM | ↓mutagenicity | [35] | |
1.2, 0.8 mM | ↑mutagenicity | ||||
Cynarin | FSF-1, | 1–50 µM | ↑viability | ↑HO-1 activity | [89] |
75–500 µM | ↓viability | ||||
hTERT-MSC | 1–00 µM | ↑viability | ↑HO-1 activity | [89] | |
75–500 µM | ↓viability | ||||
EGCG | Caenorhabditis elegans | 50–300 µM | ↑lifespan | ↑ROS; ↑AMPK/SIRT1/FOXO | [87] |
800–1000µM | ↓lifespan | ||||
Falcarinol, Falcarindiol Isolated from carrot roots | primary myotube culture/H2O2 | 1.6–25.0 μM | ↑ROS production | ↑GPx, ↓Hsp70, HO-1 | [72] |
50, 100 μM | ↓ROS production | ↓GPx, ↑Hsp70, HO-1 | |||
Falcarindiol isolated from carrot roots | primary | 0.61–9.80 nM | ↑viability | [72] | |
myotube culture | 2.5–5.0 μM | ↓viability | |||
pBMEC | ~0.04–0.20 μM | ↑proliferation | [73] | ||
~4–41 μM | ↓proliferation | ||||
CaCo-2 | 1–10 μM | ↑proliferation | ↓caspase-3, DNA breakage | [74] | |
↓apoptosis | |||||
>20 μM | ↓proliferation | ↑caspase-3, DNA breakage | |||
↑apoptosis | |||||
Glyceollin I isolated from soybean | Saccharomyces cerevisiae | 10–100 nM | ↑CLS | [82] | |
>1 μM | ↓CLS | ||||
Luteolin | MCF-7 | 1–10 μM | ↑viability | [77] | |
30–1000 μM | ↓viability | ||||
HepG2 | <35 μM | ↑LC3-II | [78] | ||
~105 μM | ↓LC3-II | ||||
Salmonella typhimurium/2-AAF | 0.006 mM | ↑mutagenicity | [35] | ||
1.2 mM | ↓mutagenicity | ||||
Nanteine isolated from Ocotea macrophilla | synaptosomal membranes | 50 μM, 0.3 mM | ↑K+ -p-NPPase activity | [84] | |
>0.75 mM | ↓K+ -p-NPPase activity | ||||
Naringenin | Drosophila melanogaster | 200, 400 μM | ↑lifespan | ↑pupae formation | [75] |
600, 800 μM | ↓lifespan | ↓pupae formation | |||
Naphazarin | Caenorhabditis elegans | 50–500 μM | ↑lifespan | ↑skn-1 | [86] |
1000 µM | ↓lifespan | ||||
Panaxatriol saponins isolated from Panax notoginseng | PC-12 | 0.03–1.00 mg/ml | ↑proliferation | [88] | |
4 mg/ml | ↓proliferation | ||||
PC-12 /6-OHDA | 0.03–2.00 mg/ml | ↑viability | ↑PI3K/AKT/mTOR ↑AMPK/SIRT1/FOXO3 | ||
4 mg/ml | ↓viability | ||||
Plumbagin | Caenorhabditis elegans | 1–45 μM | ↑lifespan | ↑skn-1 | [86] |
100 μM | ↓lifespan | ||||
Rosmarinic acid | Caenorhabditis elegans | 100–300 µM | ↑lifespan | ↑hsp | [34] |
600 µM | ↓lifespan | ||||
Rutin | Drosophila melanogaster | 200, 400 μM | ↑lifespan | ↑longevity associated genes | [76] |
600, 800 μM | ↓lifespan | ||||
Salvianolic acid B | BMSCs | ~4–111 μM | ↑metabolic activity, ALP activity | [81] | |
~223 μM | ↓metabolic activity, ALP activity | ||||
Sulforaphane | T24, HepG2, Caco-2 | 1–5 μM | ↑proliferation | ↑RAS, RAF, MEK, ERK, PI3K, AKT and Nf-kB, FOXO Nrf2 pathways | [63] |
10–40 μM | ↓proliferation | ||||
T24 | 2.50, 3.75 μM | ↑migration | |||
5–40 μM | ↓migration | ||||
HUVEC, PVC | 2.5–5.0 μM | ↑angiogenesis | ↑tube formation | ||
10, 20 μM | ↓angiogenesis | ↓tube formation | |||
Isolated from Brassica oleracea | MSCs | 0.25, 1.00 μM | ↑proliferation | [66] | |
20 μM | ↓proliferation | ||||
<5 μM | ↓apoptotic cells | ||||
20 μM | ↑apoptotic cells | ||||
0.25, 1.00 μM | ↓senescence cells | ||||
5, 20 μM | ↑senescence cells | ||||
0.25 μM | ↓ROS production | ||||
20 μM | ↑ROS production | ||||
Commercial source | MCF-7, HHL-5, HepG2, lymphoblastoid cells | <5 μM | ↑proliferation | [67,68,69] | |
>5 μM | ↓proliferation | ||||
lymphoblastoid cells | 0.5–5.0 μM | ↑GSH | [69] | ||
10 μM | ↓GSH | ||||
Umbelliprenin isolated from Ferula szowitsiana | Jurkat T-CLL | 10, 25 μM | ↑apoptosis | [83] | |
50, 100 μM | ↓apoptosis | ||||
Z-ligustilide isolated from Ligusticum chuanxiong | PC-12/ OGD | 1–25 μM | ↑viability, ↓apoptosis | ↑HO-1 and Nrf2 translocation | [79] |
50 μM | ↓viability, ↑apoptosis | ||||
Spodoptera litura larvae | 0.1–0.5 mg/g diet | ↑GST, AChE, CYP, CES activities | ↑GSTS1, CYP4S9, CYP4M14 | [80] | |
1, 5 mg/g diet | ↓GST, AChE, CYP activity | ↓GSTS1, CYP4S9, CYP4M14 |
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Jodynis-Liebert, J.; Kujawska, M. Biphasic Dose-Response Induced by Phytochemicals: Experimental Evidence. J. Clin. Med. 2020, 9, 718. https://doi.org/10.3390/jcm9030718
Jodynis-Liebert J, Kujawska M. Biphasic Dose-Response Induced by Phytochemicals: Experimental Evidence. Journal of Clinical Medicine. 2020; 9(3):718. https://doi.org/10.3390/jcm9030718
Chicago/Turabian StyleJodynis-Liebert, Jadwiga, and Małgorzata Kujawska. 2020. "Biphasic Dose-Response Induced by Phytochemicals: Experimental Evidence" Journal of Clinical Medicine 9, no. 3: 718. https://doi.org/10.3390/jcm9030718