-
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 -
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 -
Cell Biochemistry and Biophysics Nov 2014Gallbladder cancer is the most common and aggressive type of biliary tract cancer with poor prognosis due to both its inability to be detected at an early stage and its...
Gallbladder cancer is the most common and aggressive type of biliary tract cancer with poor prognosis due to both its inability to be detected at an early stage and its poor sensitivity to conventional therapies. Gemcitabine has been more and more widely used for the treatment of gallbladder cancer; however, the response rate is not satisfactory. Phenoxodiol is an isoflavone analog with antitumor activity against a variety of cancers. In our current work, we examined the effect of phenoxodiol on gallbladder cancer cells and to determine whether phenoxodiol can enhance the antitumor activity of gemcitabine in gallbladder cancer. The combined treatment of phenoxodiol and gemcitabine was more effective at inhibiting cell proliferation than either chemotherapeutic agent treatment alone. Meanwhile, phenoxodiol arrests cell cycle progression in the G0-G1 phase. In addition, phenoxodiol and gemcitabine inhibit the phosphorylation of PI3K/Akt-signaling pathway as well as modulate the expression of apoptosis-relevant molecules. Furthermore, the antitumor effect of combination treatment with phenoxodiol and gemcitabine on gallbladder cancer was evaluated using a murine gallbladder cancer xenograft model and the results suggested that phenoxodiol enhanced the in vivo antitumor activity of gemcitabine. Taken together, our study suggested that the combination treatment with phenoxodiol and gemcitabine might offer optimal therapeutic benefits for patients with gallbladder cancer.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Deoxycytidine; Drug Synergism; Female; G1 Phase Cell Cycle Checkpoints; Gallbladder Neoplasms; Humans; Isoflavones; Mice; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Resting Phase, Cell Cycle; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 24902539
DOI: 10.1007/s12013-014-0061-y -
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 -
Anticancer Research Oct 2018In the present study, the antineoplastic activity and mechanism of action of phenoxodiol, a novel isoflavone analog, was investigated in renal cancer cells.
BACKGROUND/AIM
In the present study, the antineoplastic activity and mechanism of action of phenoxodiol, a novel isoflavone analog, was investigated in renal cancer cells.
MATERIALS AND METHODS
A panel of renal cancer cells (769-P, 786-O, Caki-2) was treated with phenoxodiol in vitro, and the efficacy of treatment was evaluated.
RESULTS
MTS assay results showed that phenoxodiol decreased renal cancer viability in a dose-dependent manner. In addition, it inhibited colony formation significantly and perturbed the cell cycle. Treatment with phenoxodiol increased the number of annexin-V-positive cells as well as the expression of cleaved poly ADP ribose polymerase, demonstrating that phenoxodiol induced apoptosis in renal cancer cells. Phenoxodiol also inhibited Akt pathway via dephosphorylation of Akt.
CONCLUSION
Phenoxodiol inhibited Akt pathway and induced apoptosis of renal cancer cells. The present study provides a theoretical basis for future development of a novel therapy effective against renal cancer.
Topics: Antineoplastic Agents; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Carcinoma, Renal Cell; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Isoflavones; Kidney Neoplasms; Proto-Oncogene Proteins c-akt; Tumor Cells, Cultured
PubMed: 30275191
DOI: 10.21873/anticanres.12908 -
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 -
Naunyn-Schmiedeberg's Archives of... Oct 2019Phenoxodiol is used for the treatment of malignancy. The substance is effective by triggering suicidal tumor cell death or apoptosis. At least in theory, phenoxodiol...
Phenoxodiol is used for the treatment of malignancy. The substance is effective by triggering suicidal tumor cell death or apoptosis. At least in theory, phenoxodiol could similarly stimulate suicidal erythrocyte death or eryptosis. Eryptosis is characterized by cell shrinkage and breakdown of cell membrane asymmetry with phosphatidylserine translocation to the erythrocyte surface. Signaling of eryptosis includes increase of cytosolic Ca activity ([Ca]), formation of reactive oxygen species (ROS), and increase of ceramide abundance at the cell surface. The present study explored whether phenoxodiol induces eryptosis and whether it modifies Ca entry, ROS, and ceramide. Using flow cytometry, phosphatidylserine exposure at the cell surface was quantified from annexin V binding, cell volume from forward scatter, [Ca] from Fluo3 fluorescence, ROS from DCFDA-dependent fluorescence, and ceramide abundance utilizing specific antibodies. A 48-h exposure of human erythrocytes to phenoxodiol (100 μg/ml [416 μM]) significantly increased the percentage of annexin V binding cells, significantly decreased average forward scatter and Fluo3 fluorescence and significantly increased ceramide abundance, but did not significantly modify DCFDA fluorescence. The effect of phenoxodiol on annexin V binding tended to decrease following removal of extracellular Ca, an effect, however, not reaching statistical significance. In conclusion, phenoxodiol triggers eryptosis, an effect paralleled by increase of ceramide abundance.
Topics: Annexin A5; Antineoplastic Agents; Calcium; Ceramides; Eryptosis; Erythrocytes; Humans; Isoflavones; Reactive Oxygen Species
PubMed: 31280326
DOI: 10.1007/s00210-019-01681-8 -
Carbohydrate Polymers Jun 2017Phenoxodiol is an isoflavone analogue that possesses potent anticancer properties. However, the poor water solubility of phenoxodiol limits its overall efficacy as an...
Phenoxodiol is an isoflavone analogue that possesses potent anticancer properties. However, the poor water solubility of phenoxodiol limits its overall efficacy as an anticancer agent. To overcome this, β-cyclodextrin was used to encapsulate phenoxodiol. The phenoxodiol-β-cyclodextrin complex was prepared via a modified co-evaporation method and characterized by H NMR and X-ray crystallography, revealing a 1:2 stoichiometry. The 2D ROESY NMR spectroscopy suggested the limited motion of phenoxodiol within the cavity of β-cyclodextrin while the X-ray crystal data displays by far the best 'ship-in-a-bottle' case of 1:2 inclusion complex. The aqueous solubility of the phenoxodiol in β-cyclodextrin had improved and the in vitro biological evaluation revealed enhanced anti-proliferative activity against three cancer cell lines. Additionally, the toxicity of the complex against normal human cell line was 2.5 times lower. These data indicates that the encapsulation of phenoxodiol into β-cyclodextrin leads to an improvement in its overall water solubility and biological activity.
Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Isoflavones; Magnetic Resonance Spectroscopy; Solubility; beta-Cyclodextrins
PubMed: 28363571
DOI: 10.1016/j.carbpol.2017.02.081 -
Bioorganic & Medicinal Chemistry Letters Jun 2017Phenoxodiol is an isoflavene with potent anti-tumor activity. In this study, a series of novel mono- and di-substituted phenoxodiol-thiosemicarbazone hybrids were...
Phenoxodiol is an isoflavene with potent anti-tumor activity. In this study, a series of novel mono- and di-substituted phenoxodiol-thiosemicarbazone hybrids were synthesized via the condensation reaction between phenoxodiol with thiosemicarbazides. The in vitro anti-proliferative activities of the hybrids were evaluated against the neuroblastoma SKN-BE(2)C, the triple negative breast cancer MDA-MB-231, and the glioblastoma U87 cancer cell lines. The mono-substituted hybrids exhibited potent anti-proliferative activity against all three cancer cell lines, while the di-substituted hybrids were less active. Selected mono-substituted hybrids were further investigated for their cytotoxicity against normal MRC-5 human lung fibroblast cells, which identified two hybrids with superior selectivity for cancer cells over normal cells as compared to phenoxodiol. This suggests that mono-substituted phenoxodiol-thiosemicarbazone hybrids have promising potential for further development as anti-cancer agents.
Topics: Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Isoflavones; Thiosemicarbazones
PubMed: 28408225
DOI: 10.1016/j.bmcl.2017.04.002 -
Cancer Cell International 2014Prostate cancer is associated with a poor survival rate. The ability of cancer cells to evade apoptosis and exhibit limitless replication potential allows for...
BACKGROUND
Prostate cancer is associated with a poor survival rate. The ability of cancer cells to evade apoptosis and exhibit limitless replication potential allows for progression of cancer from a benign to a metastatic phenotype. The aim of this study was to investigate in vitro the effect of the isoflavone phenoxodiol on the expression of cell cycle genes.
METHODS
Three prostate cancer cell lines-LNCaP, DU145, and PC3 were cultured in vitro, and then treated with phenoxodiol (10 μM and 30 μM) for 24 and 48 h. The expression of cell cycle genes p21(WAF1), c-Myc, Cyclin-D1, and Ki-67 was investigated by Real Time PCR.
RESULTS
Here we report that phenoxodiol induces cell cycle arrest in the G1/S phase of the cell cycle, with the resultant arrest due to the upregulation of p21(WAF1) in all the cell lines in response to treatment, indicating that activation of p21(WAF1) and subsequent cell arrest was occurring via a p53 independent manner, with induction of cytotoxicity independent of caspase activation. We found that c-Myc and Cyclin-D1 expression was not consistently altered across all cell lines but Ki-67 signalling expression was decreased in line with the cell cycle arrest.
CONCLUSIONS
Phenoxodiol demonstrates an ability in prostate cancer cells to induce significant cytotoxicity in cells by interacting with p21(WAF1) and inducing cell cycle arrest irrespective of p53 status or caspase pathway interactions. These data indicate that phenoxodiol would be effective as a potential future treatment modality for both hormone sensitive and hormone refractory prostate cancer.
PubMed: 25400509
DOI: 10.1186/s12935-014-0110-z