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Frontiers in Oncology 2022Cancer is one of the major health problems and the second cause of death worldwide behind heart disease. The traditional soy diet containing isoflavones, consumed by the... (Review)
Review
Cancer is one of the major health problems and the second cause of death worldwide behind heart disease. The traditional soy diet containing isoflavones, consumed by the Asian population in China and Japan has been identified as a protective factor from hormone-related cancers. Over the years the research focus has shifted from emphasizing the preventive effect of isoflavones from cancer initiation and promotion to their efficacy against established tumors along with chemo- and radiopotentiating effects. Studies performed in mouse models and results of clinical trials emphasize that genistein or a mixture of isoflavones, containing in traditional soy diet, could be utilized to both potentiate the response of cancer cells to radiotherapy and reduce radiation-induced toxicity in normal tissues. Currently ongoing clinical research explores a potential of another significant isoflavone, idronoxil, also known as phenoxodiol, as radiation enhancing agent. In the light of the recent clinical findings, this article reviews the accumulated evidence which support the clinically desirable interactions of soy isoflavones with radiation therapy resulting in improved tumor treatment. This review discusses important aspects of the development of isoflavones as anticancer agents, and mechanisms potentially relevant to their activity in combination with radiation therapy of cancer. It gives a critical overview of studies characterizing isoflavone targets such as topoisomerases, ENOX2/PMET, tyrosine kinases and ER receptor signaling, and cellular effects on the cell cycle, DNA damage, cell death, and immune responses.
PubMed: 36936272
DOI: 10.3389/fonc.2022.800562 -
Enzyme and Microbial Technology Nov 2022Isoflavonoids are of great interest due to their human health-promoting properties, which have resulted in studies on exploiting these phytochemicals as hotspots in...
Isoflavonoids are of great interest due to their human health-promoting properties, which have resulted in studies on exploiting these phytochemicals as hotspots in diverse bio -industries. Biocatalytic glycosylation of isoflavonoid aglycones to glycosides has attracted marked interests because it enable the biosynthesis of isoflavonoid glycosides with high selectivity under mild conditions, and also provide an environmentally friendly option for the chemical synthesis. Thus, these inspired us to exploit new flexible and effective glycosyltransferases from microbes for making glycosides attractive compounds that are in high demand in several industries. Most recently, we have reported the functional characterization of a bacterial-origin recombinant glycosyltransferase (MeUGT1). Herein, more detailed kinetic characteristics of this biocatalyst, using a number of glycosyl donor substrates, were examined for further investigation of its biocatalytic applicability, enabling it feasible to biosynthesize new glycosides; phenoxodiol-4'-O-α-glucuronide, phenoxodiol-4'-O-α-(2''-N-acetyl)glucosaminide, phenoxodiol-4'-O-α-galactoside, phenoxodiol-4'-O-α-(2''-N-acetyl)galactosaminide and phenoxodiol-4'-O-α-(2''-deoxy)glucoside. The thorough kinetic analyses revealed that while the recombinant enzyme can utilize, albeit with different substrate preference and catalytic efficiency, a total five different nucleotide sugars as glycosyl donors, exhibiting its promiscuity towards glycosyl donors. This is the first report that a recombinant glycosyltransferase MeUGT1 that can regio-specifically glycosylate C4'-hydroxyl function of semi-synthetic phenoxodiol isoflavene to biosynthesize a series of unnatural phenoxodiol-4'-O-α-glycosides.
Topics: Glycosides; Glycosylation; Glycosyltransferases; Humans; Isoflavones
PubMed: 35998478
DOI: 10.1016/j.enzmictec.2022.110113 -
Journal of Microbiology and... May 2022Glycosyltransferase (GT)-specific degenerate PCR screening followed by in silico sequence analyses of the target clone was used to isolate a member of family1...
Glycosyltransferase (GT)-specific degenerate PCR screening followed by in silico sequence analyses of the target clone was used to isolate a member of family1 GT-encoding genes from the established fosmid libraries of soil actinomycetes ATCC 27932. A recombinant MeUGT1 was heterologously expressed as a His-tagged protein in , and its enzymatic reaction with semi-synthetic phenoxodiol isoflavene (as a glycosyl acceptor) and uridine diphosphate-glucose (as a glycosyl donor) created two different glycol-attached products, thus revealing that MeUGT1 functions as an isoflavonoid glycosyltransferase with regional flexibility. Chromatographic separation of product glycosides followed by the instrumental analyses, clearly confirmed these previously unprecedented glycosides as phenoxodiol-4'-α--glucoside and phenoxodiol-7-α--glucoside, respectively. The antioxidant activities of the above glycosides are almost the same as that of parental phenoxodiol, whereas their anti-proliferative activities are all superior to that of cisplatin (the most common platinum chemotherapy drug) against two human carcinoma cells, ovarian SKOV-3 and prostate DU-145. In addition, they are more water-soluble than their parental aglycone, as well as remaining intractable to the simulated in vitro digestion test, hence demonstrating the pharmacological potential for the enhanced bio-accessibility of phenoxodiol glycosides. This is the first report on the microbial enzymatic biosynthesis of phenoxodiol glucosides.
Topics: Escherichia coli; Glucosides; Glycosides; Glycosylation; Glycosyltransferases; Humans; Isoflavones; Male; Micromonospora
PubMed: 35131959
DOI: 10.4014/jmb.2111.11032 -
British Journal of Pharmacology Mar 2022Recently, isoflavone derivatives have been shown to have neuroprotective effects against neurological disorders. For instance, genistein attenuated the neuroinflammation...
BACKGROUND AND PURPOSE
Recently, isoflavone derivatives have been shown to have neuroprotective effects against neurological disorders. For instance, genistein attenuated the neuroinflammation and amyloid-β accumulation in Alzheimer's disease animal models, suggesting the potential for use to prevent and treat Alzheimer's disease.
EXPERIMENTAL APPROACH
Here, 50 compounds, including isoflavone derivatives, were constructed and screened for the inhibitory effects on amyloid-β fibrilization and oligomerization using the high-throughput screening formats of thioflavin T assay and multimer detection system, respectively. The potential neuroprotective effect of t3-(4-hydroxyphenyl)-2H-chromen-7-ol (SPA1413), also known as dehydroequol, idronoxil or phenoxodiol, was evaluated in cells and in 5xFAD (B6SJL) transgenic mouse, a model of Alzheimer's disease.
KEY RESULTS
SPA1413 had a potent inhibitory action on both amyloid-β fibrilization and oligomerization. In the cellular assay, SPA1413 prevented amyloid-β-induced cytotoxicity and reduced neuroinflammation. Remarkably, the oral administration of SPA1413 ameliorated cognitive impairment, decreased amyloid-β plaques and activated microglia in the brain of 5xFAD (B6SJL) transgenic mouse.
CONCLUSION AND IMPLICATIONS
Our results strongly support the repurposing of SPA1413, which has already received fast-track status from the US Food and Drug Administration (FDA) for cancer treatment, for the treatment of Alzheimer's disease due to its potent anti-amyloidogenic and anti-neuroinflammatory actions.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Isoflavones; Mice; Mice, Transgenic; Neuroprotective Agents; Plaque, Amyloid
PubMed: 34610141
DOI: 10.1111/bph.15691 -
Molecules (Basel, Switzerland) Aug 2020Some aromatic polyketides such as dietary flavonoids have gained reputation as miraculous molecules with preeminent beneficial effects on human health, for example, as... (Review)
Review
Some aromatic polyketides such as dietary flavonoids have gained reputation as miraculous molecules with preeminent beneficial effects on human health, for example, as antioxidants. However, there is little conclusive evidence that dietary flavonoids provide significant leads for developing more effective drugs, as the majority appears to be of negligible medicinal importance. Some aromatic polyketides of limited distribution have shown more interesting medicinal properties and additional research should be focused on them. Combretastatins, analogues of phenoxodiol, hepatoactive kavalactones, and silymarin are showing a considerable promise in the advanced phases of clinical trials for the treatment of various pathologies. If their limitations such as adverse side effects, poor water solubility, and oral inactivity are successfully eliminated, they might be prime candidates for the development of more effective and in some case safer drugs. This review highlights some of the newer compounds, where they are in the new drug pipeline and how researchers are searching for additional likely candidates.
Topics: Antioxidants; Clinical Trials as Topic; Flavonoids; Humans; Polyketides
PubMed: 32847100
DOI: 10.3390/molecules25173846 -
EXCLI Journal 2020Colorectal cancer (CRC) is one of the most common types of cancer seen in the world. 5-Fluorouracil (5-Fu) plus Oxaliplatin (1-OHP) remains the backbone of CRC...
Colorectal cancer (CRC) is one of the most common types of cancer seen in the world. 5-Fluorouracil (5-Fu) plus Oxaliplatin (1-OHP) remains the backbone of CRC chemotherapeutics, but with limited success. Phenoxodiol (Pxd) is an isoflavone analog with antitumor activity against various types of cancers, and sensitizes chemoresistant cancer cells to chemotherapeutics including platinum and taxanes. This study was, therefore, undertaken to examine whether Pxd pre-treatment with conventional chemotherapeutic agent(s) 5-Fu and 1-OHP co-administration be a therapeutic strategy for CRC. Cell viability and cytotoxicity were evaluated using dimethyl-thiazolyl diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase assays. The percentage of apoptotic and necrotic cells were determined by fluorescence microscopy analysis. Besides, active Caspase-3 levels by ELISA and relative mRNA levels of Caspase 3 (), CASP8 and CASP9 genes were determined by quantitative real-time PCR (qPCR) analysis. The pre-treatment of Pxd followed by 5-Fu and 1-OHP co-administration was more effective at inhibiting cell viability than either chemotherapeutic agents treatment alone. When compared to 5-Fu with 1-OHP alone treatment, Pxd pre-treatment overwhelmingly increased apoptotic Caspase-3 activity levels in CRC cells. Moreover, qPCR analyses showed that and mRNA levels significantly increased after pre-treatment with Pxd followed by 5-Fu and 1-OHP treatments, compared to 5-Fu with 1-OHP alone. Our results suggested that Pxd enhanced the antitumor activity of 5-Fu and 1-OHP. Our study also suggested that Pxd may be a potential candidate agent in advanced CRC and inclusion of Pxd to the conventional chemotherapeutic agent(s) could be an effective therapeutic strategy for CRC.
PubMed: 32665777
DOI: 10.17179/excli2020-2042 -
Journal of Food Science Jun 2020Brassica tournefortii is an annual herbaceous plant, native to the North Africa and Middle East. It is considered as an excellent medicinal plant due to its richness by...
Brassica tournefortii is an annual herbaceous plant, native to the North Africa and Middle East. It is considered as an excellent medicinal plant due to its richness by antioxidant like isothiocyanates and polyphenols. The present study is the first phytochemical investigation on Brassica tournefortii organs (leaves, stems, and roots) in terms of nutraceutical, chemical composition, and bioactivity. Brassica tournefortii leaves exhibited the highest values of nutraceutical contents. Interestingly, gas chromatograph-y-mass spectrometry (GC-MS) analysis enabled to identify three new isothiocyanates: iberverin nitrile and iberin detected only in roots, and iberin nitrile detected in all organs. HPLC chromatograms displayed different profiles depending on organic solvent and extracted organ. Icariin and 5,7-dihydroxy 4-propylcoumarin showed the highest concentrations with 2.3 and 1.3 mg/g of dr among other molecules identified by high performance liquid chromatography (HPLC). Some phenolic compounds were identified in more than one organ extracts such as phenoxodiol and 4-hydroxy-3-propylbenzoic acid methyl ester. Brassica tournefortii extracts showed a moderate total phenolic contents and anti-15-LOX activity, while they exhibited a good anti-α-glucosidase activity ranging from 40% to 60%. Furthermore, leaves-MeOH and root-dichloromethane (DCM) extracts induced the highest cytotoxicity against MCF-7 cell lines, while roots-cyclohexane (CYHA) extract highlighted the highest inhibition activity against, both, HCT-116 and OVCAR cell lines.
Topics: Antioxidants; Cell Line; Cell Survival; Chromatography, High Pressure Liquid; Dietary Supplements; Gas Chromatography-Mass Spectrometry; Humans; Mustard Plant; Phytochemicals; Plant Extracts; Plant Leaves; Polyphenols
PubMed: 32476145
DOI: 10.1111/1750-3841.15157 -
Current Cancer Drug Targets 2020Idronoxil has been the subject of more than 50 peer-reviewed publications over the last two decades. This isoflavone is an intriguing regulator of multiple signal... (Review)
Review
Idronoxil has been the subject of more than 50 peer-reviewed publications over the last two decades. This isoflavone is an intriguing regulator of multiple signal transduction pathways, capable of causing a range of biological effects, including cell cycle arrest, apoptosis, an ability to stimulate the immune system, and inhibition of angiogenesis. These multifaceted actions suggest that idronoxil has the potential to synergize with, or complement, a wide range of cancer therapies. Whilst clinically tested in the past, idronoxil's journey was discontinued as a result of its low bioavailability in humans when administered either intravenously or orally, though strategies to overcome this issue are currently being explored. Here, we summarize the current literature regarding the key cellular targets of idronoxil and the mechanisms by which idronoxil exerts its anticancer effects, laying a new foundation toward giving this unique molecule a second chance of contributing to the future of cancer treatment.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Humans; Isoflavones; Neoplasms; Signal Transduction
PubMed: 31899676
DOI: 10.2174/1568009620666200102122830 -
Frontiers in Bioengineering and... 2019Phenoxodiol, an isoflavene anti-tumor agent, was conjugated on the polysaccharide dextran using immobilized laccase as biocatalyst. The success of the enzymatic...
Phenoxodiol, an isoflavene anti-tumor agent, was conjugated on the polysaccharide dextran using immobilized laccase as biocatalyst. The success of the enzymatic conjugation was determined by UV-vis spectrophotometry and its functionalization degree was assessed by H NMR and was found to be 3.25 mg phenoxodiol/g of conjugate. An accelerated stability test showed that the resultant conjugate was nine times more stable than the free phenoxodiol when tested for its residual anti-oxidant activity with the Folin-Ciocalteu assay. The anti-proliferative activity of the conjugate was evaluated against neuroblastoma SKN-BE(2)C, triple-negative breast cancer MDA-MB-231, and glioblastoma U87 cancer cells. The conjugate was shown to be generally more potent than phenoxodiol against all three cell types tested. Additionally, the cytotoxicity and anti-angiogenic activity of the conjugate were also evaluated against non-malignant human lung fibroblast MRC-5 and human microvascular endothelial cells HMEC-1, respectively. The conjugate was found to be 1.5 times less toxic than phenoxodiol while mostly retaining 62% of its anti-angiogenic activity in the conjugate form. This study provides further evidence that the conjugation of natural product-derived drugs onto polysaccharide molecules such as dextran can lead to better stability and enhanced biological activity of the conjugate compared to the free drug alone.
PubMed: 31440502
DOI: 10.3389/fbioe.2019.00183 -
Naunyn-Schmiedeberg's Archives of... Oct 2019The original version of this article contains several mistakes due to the missed corrections.
The original version of this article contains several mistakes due to the missed corrections.
PubMed: 31332477
DOI: 10.1007/s00210-019-01693-4