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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 -
Advances in Cancer Research 2019Isoflavones isolated from members of the Fabaceae (primarily Leguminosae) family have been characterized for their phytoestrogenic properties, but certain derivatives...
Isoflavones isolated from members of the Fabaceae (primarily Leguminosae) family have been characterized for their phytoestrogenic properties, but certain derivatives have also shown potential as possible cancer therapeutic agents. ME-344, related to phenoxodiol (Fig. 1), is a second generation isoflavone with a recent history of both preclinical and early clinical testing. The drug has unusual cytotoxicity profiles, where cancer cell lines can be categorized as either intrinsically sensitive or resistant to the drug. Evolving studies show that the cytotoxic properties of the drug are enacted through targeting mitochondrial bioenergetics. While the drug has undergone early Phase I/II trials in solid tumors with confined dose limiting effects and some evidence of disease response, there is a continuing need to define specific cellular targets that determine sensitivity, with the long-term goal of applying such information to individualized therapy. This review article details some of the existing and ongoing studies that are assisting in the continued drug development processes that may lead to new drug application (NDA) status.
Topics: Antineoplastic Agents; Apoptosis; Clinical Trials, Phase I as Topic; Drug Screening Assays, Antitumor; Humans; Isoflavones; Neoplasms
PubMed: 30885362
DOI: 10.1016/bs.acr.2019.01.005 -
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 -
Anticancer Research Jan 2018To investigate whether XIAP down-regulation and autophagy inhibition sensitize ovarian clear cell cancer cells to cisplatin.
BACKGROUND/AIM
To investigate whether XIAP down-regulation and autophagy inhibition sensitize ovarian clear cell cancer cells to cisplatin.
MATERIALS AND METHODS
The ovarian clear cancer cell line KK was used for in vitro analysis. Hydroxychloroquine (HCQ) and phenoxodiol (PXD) or embelin were used as autophagy and XIAP inhibitors, respectively. Non-specific and XIAP-specific siRNAs were transfected using Lipofectamine. Cytotoxicity was assessed by MTT assays. Protein expression was confirmed by western blotting.
RESULTS
In KK, down-regulation of XIAP using specific siRNAs together with HCQ treatment enhanced the anti-tumor effect of cisplatin. Although embelin sensitized KK to cisplatin through XIAP down-regulation, it induced autophagy. However, PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition. Expression of Atg7, Atg12, and Beclin 1 was decreased after PXD treatment.
CONCLUSION
PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition and could be a new candidate for ovarian clear cell carcinoma treatment.
Topics: Adenocarcinoma, Clear Cell; Antineoplastic Agents; Autophagy; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Down-Regulation; Female; Humans; Isoflavones; Ovarian Neoplasms; RNA, Small Interfering; X-Linked Inhibitor of Apoptosis Protein
PubMed: 29277787
DOI: 10.21873/anticanres.12222 -
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 -
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 -
Cancer Chemotherapy and Pharmacology Feb 2017Recurrent, chemo-resistant ovarian cancer is thought to be due to a subgroup of slow-growing, drug-resistant cancer cells with stem-like properties and a high capacity... (Review)
Review
PURPOSE
Recurrent, chemo-resistant ovarian cancer is thought to be due to a subgroup of slow-growing, drug-resistant cancer cells with stem-like properties and a high capacity for tumour repair. Cantrixil targets this sub-population of cells and is being developed as an intraperitoneal therapy to be used as first-line therapy in combination with carboplatin for epithelial ovarian cancer. The studies presented here justify further development.
METHODS
A GLP dog CV study using a 4 × 4 Latin Square Crossover study was conducted using telemetric ECG recordings from dogs post IP administration to assess for cardiac abnormalities. Mutagenic potential was assessed using the bacterial reverse mutation assay. Clastogenicity was assessed by determining micronuclei formation in the bone marrow of SPF Arc(S) Swiss mice dosed at clinical concentrations. TRX-E-002-1 toxicology was evaluated in GLP-compliant MTD and 28-day repeat-dose studies in rats and dogs.
RESULTS
In vitro TRX-E-002-1 has potent cytotoxic activity against human cancer cells including CD44+/MyD88+ ovarian cancer stem cells. TRX-E-002-1 increased phosphorylated c-Jun levels in these cancer cells resulting in caspase-mediated apoptosis. In vivo, Cantrixil was active in a model of disseminated ovarian cancer as a monotherapy and in combination with Cisplatin. Cantrixil was active as maintenance therapy in a model of drug-resistant, recurrent ovarian cancer and in an orthotopic model of pancreatic cancer.
CONCLUSIONS
In animals, this clinical formulation and route of administration of Cantrixil demonstrated acceptable activity, safety pharmacology, genotoxicity and toxicology profile and constituted a successful Investigational New Drug application to the US Food and Drug Administration.
Topics: Animals; Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Cross-Over Studies; Dogs; Drug Interactions; Flavonoids; Humans; Mice; Rats; Species Specificity
PubMed: 28013349
DOI: 10.1007/s00280-016-3224-2 -
Journal of Biological Regulators and... 2016Cancer includes a number of related diseases due to abnormal cell proliferation that spreads to nearby tissues. Many compounds (physical, chemical and biological) have...
Cancer includes a number of related diseases due to abnormal cell proliferation that spreads to nearby tissues. Many compounds (physical, chemical and biological) have been used to try to halt this abnormal proliferation, but the therapeutic results are poor, due also to the side effects. It has been reported that ecto-nicotinamide adenine dinucleotide oxidase di-sulfide-thiol exchanger 2 (ENOX2), also known as tumor-associated nicotinamide adenine dinucleotide oxidase (tNOX), was found to be located on the cancer cell surface, essential for cancer cell growth. Capsaicin and other anti-oxidants are capable of inhibiting tNOX, causing apoptosis of cells, exerting anti-tumor activity. It is interesting that some authors reported that ENOX2 is present in the serum of cancer patients several years before the clinical symptoms of the tumor. However, this result has to be confirmed. In this article we discuss ENOX2 and its inhibition as a hope of improving cancer therapy.
Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Biomarkers, Tumor; Capsaicin; Catechin; Down-Regulation; Early Detection of Cancer; Enzyme Induction; Gene Expression Regulation, Neoplastic; Humans; Isoflavones; NAD; NADH, NADPH Oxidoreductases; Neoplasm Proteins; Neoplasms
PubMed: 27655481
DOI: No ID Found -
Bioorganic & Medicinal Chemistry Letters Nov 2015Phenoxodiol, an analogue of the isoflavone natural product daidzein, is a potent anti-cancer agent that has been investigated for the treatment of hormone dependent...
Phenoxodiol, an analogue of the isoflavone natural product daidzein, is a potent anti-cancer agent that has been investigated for the treatment of hormone dependent cancers. This molecular scaffold was reacted with different primary amines and secondary amines under different Mannich conditions to yield either benzoxazine or aminomethyl substituted analogues. These processes enabled the generation of a diverse range of analogues that were required for structure-activity relationship (SAR) studies. The resulting Mannich bases exhibited prominent anti-proliferative effects against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. Further cytotoxicity studies against MRC-5 normal lung fibroblast cells showed that the isoflavene analogues were selective towards cancer cells.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Female; Fibroblasts; Humans; Inhibitory Concentration 50; Isoflavones; Mannich Bases; Molecular Structure; Structure-Activity Relationship
PubMed: 26432036
DOI: 10.1016/j.bmcl.2015.09.027 -
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