Evidence for Multilevel Chemopreventive Activities of Natural Phenols from Functional Genomic Studies of Curcumin, Resveratrol, Genistein, Quercetin, and Luteolin
Abstract
:1. Introduction
1.1. Curcumin, Resveratrol, Genistein, Quercetin, and Luteolin Are Small Natural Phenols That Are Important for Chemoprevention
1.2. Chemical and Biochemical Activities of the Natural Phenols
1.3. Carcinogenesis
1.4. Apoptosis
2. Results of Functional Genomic Studies of Natural Phenols
2.1. Natural Phenols Induce Apoptosis in Cancer Cell Lines in a P53-Dependent Manner
2.2. Natural Phenols as Potent Regulators of Expression of Oncogenic and Anti-Oncogenic microRNAs
2.3. Natural Phenols as Dietary Epidrugs
2.4. Epigenetic Changes Induced by Natural Phenols in Cancer Cells Switch off Oncogenes and Switch on Anti-Oncogenes
2.5. Similar Results Can Be Obtained for Other Natural Phenols
2.5.1. Genistein
2.5.2. Quercetin
2.5.3. Luteolin
3. Conclusions
Funding
Conflicts of Interest
References
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Compound | Articles | Reviews | Clinical Trials | Supplements |
---|---|---|---|---|
Curcumin | 7157 | 1324 | 86 | 318 |
Resveratrol | 4393 | 1067 | 22 | 214 |
Genistein | 3474 | 489 | 33 | 15 |
Quercetin | 4019 | 509 | 20 | 310 |
Luteolin | 1048 | 102 | 3 | 100 |
Compound | Synonyms | Reactive Group | PubChem * Reference | PubChem ID | Molecular Formula |
---|---|---|---|---|---|
Curcumin | Diferuloylmethane | Ether, ketone, phenol, unsaturated aliphatic hydrocarbon, hydroxyl | [9] | 969516 | C21H20O6 |
Resveratrol | 3, 4′, 5-Trihydroxystilbene | Stilbene, phenol, hydroxyl | [10] | 445154 | C14H12O3 |
Genistein | 4′, 5, 7-Trihydroxyisoflavone | Phenol, hydroxyl, ketone | [11] | 5280961 | C15H10O5 |
Quercetin | 3, 3′, 4′, 5, 7-Pentahydroxyflavone | Phenol, hydroxyl, ketone | [12] | 5280343 | C15H10O7 |
Luteolin | 3′, 4′, 5, 7-Tetrahydroxyflavone | Phenol, hydroxyl, ketone | [13] | 5280445 | C15H10O6 |
Technological Platform | Cell Line and Treatment Conditions | Reported Mechanism | Other Conclusions | Reference |
---|---|---|---|---|
LD-microarray profiling expression of coding genes. | LNCaP human prostate adenocarcinoma cells (androgen-sensitive, p53 wt/wt). | Resveratrol induced the intrinsic apoptosis pathway (but only at the highest concentration tested). | At intermediate concentrations, resveratrol modulated cell cycle regulatory genes, and down-regulated markers of cellular proliferation. (At the lowest concentrations, resveratrol stimulated viability suggesting a hormetic response curve.) | [47] |
The phytochemical was applied in cell media in increasing concentrations: 0.01, 0.1, 1, 10, 25, 40, and 100 μM. | The activation of p53-dependant apoptosis was evident by the transcriptional upregulation of p21 and MDM2. | Resveratrol also had a strong inhibitory effect on the androgen pathway (which included prostate-specific antigen—PSA). | ||
HD-microarray profiling expression of coding genes. | The following human lung cancer cells were used: NCI H460 (p53 wt/wt), NCI H23 (with a homozygous missense mutation: methionine to isoleucine at codon 246), and A549 (p53 wt/wt). | Resveratrol induced the intrinsic apoptosis pathway in wild-type A549 cells. | Resveratrol also inhibited growth of the p53 mutated cancer cell line (NCI H23) suggesting that it can also induce p53-independent apoptosis or cell cycle arrest. | [48] |
25 μM phytochemical was applied in cell media (with the incubation time of 48 h). | The activation of p53-dependant apoptosis was evident by transcriptional upregulation of p21 and p27. | |||
Human fibrosarcoma cells: HT1080 (p53 wt/wt). | Resveratrol induced the intrinsic apoptosis pathway. | Resveratrol also modulated the expression of genes associated with cell cycle, cytoskeleton, and cell-adhesion. | [49] | |
The phytochemical was applied at 2195 ng/mL in media (with the incubation time of six hours). | The activation of p53-dependant apoptosis was evident by differential regulation of 13 genes in the KEGG’s p53 signaling pathway. | |||
MDA-MB-231 human breast cancer cell line (estrogen receptor negative). | Resveratrol induced the intrinsic apoptosis pathway. | There was also evidence for cell cycle arrest (increased fraction of cells in the G1 phase and inhibition of the expression of cyclin B1). | [50] | |
10 μM phytochemical was applied in cell media (with the incubation time of six hours). | The activation of the p53-dependant apoptosis was evident by transcriptional upregulation of p21, PIG3, and BAD. | |||
Human renal carcinoma cells of likely proximal tubule origin. (These cells are known to have a p53 wt/wt genotype, but p53 signaling is strongly repressed.) | Resveratrol induced the intrinsic apoptosis pathway. | Fifteen-fold induction of tumor necrosis factor α inducible protein 3 (TNFAIP3) also suggested the induction of the extrinsic apoptosis pathway. | [51] | |
50 μM phytochemical was applied in cell media (with the incubation time of 24 h). | The activation of the p53-dependant apoptosis was evident by sevenfold transcriptional upregulation of MDM2. |
Technological Platform | Cell Line and Treatment Conditions | Reported Mechanism | Other Conclusions | Reference |
---|---|---|---|---|
LD-microarray profiling expression of coding genes. | MCF-7 human breast adenocarcinoma (p53 wt/wt). | Resveratrol induced the intrinsic apoptosis pathway. | Changes in expression of some apoptosis-related genes were dependent on the concentration of curcumin: shifting in opposite directions at the low versus the high concentration. (This might suggest hormetic effects.) | [52] |
The activation of the p53-dependant apoptosis was evident by transcriptional up-regulation of CASP1, CASP2, CASP3, CASP4, BCL2L2, PIG3, and PIG11. | ||||
Cells were incubated in media with 0, 25, or 50 μg/mL phytochemical (applied for 24 h). | ||||
Observed changes also suggested indirect activation of apoptosis by down-regulation of pro-survival signals from growth factors and apoptosis inhibitors. | ||||
HD-microarray profiling expression of coding genes. | Hepatocellular carcinoma cell lines: KMCH, WRL68, Huh7, PLC, and Pitts1. | Curcumin indirectly promoted apoptosis by silencing pro-survival oncogenic signaling, in particular the NF-κB pathway. | Curcumin also modulated MYC signaling, which is known to have mixed effects (partially mitogenic and partially pro-apoptotic). Curcumin also modulated genes involved in cytokine signaling, growth factor signaling, and the regulation of angiogenesis. | [53] |
Cells were incubated with 25 μM phytochemical (applied for 72 h). | ||||
A microarray profiling microRNAs (miRCURY). | Several human cell lines originating from non-small cell lung cancers. | Resveratrol induced the intrinsic apoptosis pathway. | Altogether, six microRNAs were up regulated by the curcumin treatment: miR-132-3p, miR-183-5p, miR-124-3p, miR-215, miR-192-5p, and miR-194-5p. Moreover, two microRNAs were down regulated (i.e., miR-602 and miR-223-3p). | [54] |
The activation of the p53-dependant apoptosis was evident by up-regulation of pro-apoptotic miR-192-5p and miR-215. | ||||
The microRNAs acts similarly to protein-coding anti-oncogenes inducing apoptosis in transformed cells. The induction of apoptosis involved the down-regulation of a known inhibitor of the intrinsic apoptosis pathway: X-linked inhibitor of apoptosis protein (XIAP—which normally binds and blocks initiator caspase 9). The resulting activation of the initiator caspase, in turn, led to the activation of effector caspases (in particular caspase-3) that rapidly effected cell death. | ||||
Cells were incubated with 15 μM curcumin for 48 h. |
Compound | Cancer Model | Chip | Data |
---|---|---|---|
Resveratrol | Prostate adenocarcinoma cell line [47] | LD-microarray with 30,000 UniGene clusters | GSE4399 |
Non-small cell lung cancer [48] | Human Genome U133 Plus 2.0 Array (Affymetrix) | GDS2966 | |
Fibrosarcoma cell line [49] | Human Genome U133 Plus 2.0 Array (Affymetrix) | GSE59704 | |
Breast adenocarcinoma [50] | HD-microarray | n/a | |
Kidney carcinoma [51] | LD-microarray | n/a | |
Curcumin | Breast adenocarcinoma [52] | LD-microarray, 4069 I.M.A.G.E. clones spotted on microscopic slides | n/a |
Liver hepatocellular carcinoma [53] | Human HT-12 V4.0 expression Beadchip (Illumina) | GSE59713 | |
Non-small cell lung cancer [54] | MicroRNA microarray | n/a |
Compound | Cancer Model | Chip | Data |
---|---|---|---|
Genistein | Prostate specimens from a clinical trial of genistein supplementation prior to prostatectomy [88] | HumanHT-12 v4 Expression BeadChip, HumanMethylation450 (Illumina) | GSE84748, GSE84749 |
Rat mammary epithelial cells [89] | Rat 230A GeneChip (Affymetrix) | GSE6879 | |
Prostate cancer cell line [90] | SurePrint G3 Human GE 8 × 60K Microarray (Agilent) | GSE29079 | |
Human embryonic kidney cell line—HEK293, and breast cancer cell line—MCF-7 [91] | 14K microarray slides printed at the University of Calgary | GSE6199, GSE6200 | |
Women with invasive breast adenocarcinoma [92] | Human U133 Plus 2.0 chip (Affymetrix) | GSE58792 | |
Daidzein | H1299 lung cancer cells [93] | Capital Bio Technology human long non-coding RNA Array v4 | GSE181093 |
Quercetin | HepG2 hepatocellular carcinoma cell line and breast adenocarcinoma T47D cells [94] | Human U133A Plus 2 chip (Affymetrix) | GSE15162 |
Distal colon mucosa of rats [95] | Rat Genome 230 2.0 Array (Affymetrix) | GSE7479 | |
Neuroblastoma cells in vitro [91] | GSE6200 | ||
Luteolin | Prostate cancer cell line [96] | SurePrint Human v18.0 miRNA array, whole human genome oligonucleotide microarrays (Agilent) | GSE53180, GSE53178 |
Mouse xenograft model of head and neck squamous cell carcinoma [97] | SurePrint G3 Human GE v2 8 × 60K array, human miRNA microarray (Agilent) | GSE75029 |
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Huminiecki, L. Evidence for Multilevel Chemopreventive Activities of Natural Phenols from Functional Genomic Studies of Curcumin, Resveratrol, Genistein, Quercetin, and Luteolin. Int. J. Mol. Sci. 2022, 23, 14957. https://doi.org/10.3390/ijms232314957
Huminiecki L. Evidence for Multilevel Chemopreventive Activities of Natural Phenols from Functional Genomic Studies of Curcumin, Resveratrol, Genistein, Quercetin, and Luteolin. International Journal of Molecular Sciences. 2022; 23(23):14957. https://doi.org/10.3390/ijms232314957
Chicago/Turabian StyleHuminiecki, Lukasz. 2022. "Evidence for Multilevel Chemopreventive Activities of Natural Phenols from Functional Genomic Studies of Curcumin, Resveratrol, Genistein, Quercetin, and Luteolin" International Journal of Molecular Sciences 23, no. 23: 14957. https://doi.org/10.3390/ijms232314957