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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 -
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 -
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 -
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 -
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 -
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 -
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 -
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 -
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 -
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