Potent Antiangiogenic Activity Research Articles

Targeting Radiation Resistance in Oesophageal Adenocarcinoma with Pyrazinib-Functionalised Gold Nanoparticles.

To overcome these limitations, pyrazinib was conjugated with gold nanoparticles (AuNP-P3), creating a novel formulation designed to enhance solubility, maintain bioactivity, and enable targeted delivery to tumour sites. In an isogenic model of OAC radioresistance, AuNP-P3 significantly reduced the surviving fraction following irradiation, demonstrating its radiosensitizing properties. It also reduced mitochondrial metabolism and modulated the secretion of inflammatory mediators in both in vitro models of OAC radioresistance and human ex vivo OAC tumour explants. Furthermore, AuNP-P3 exhibited potent anti-angiogenic activity, significantly inhibiting blood vessel formation in vivo using zebrafish embryo models. These results collectively confirm that P3, in its conjugated formulation with gold nanoparticles, retains its therapeutic properties, highlighting the potential of AuNP-P3 as a novel therapeutic radiosensitizer for oesophageal adenocarcinoma and supporting its further development for clinical applications.

Interleukin-12 treatment reduces tumor growth and modulates the expression of CASKA and MIR-203 in athymic mice bearing tumors induced by the HGC-27 gastric cancer cell line

Gastric cancer (GC) is one of the most common malignant tumors in the digestive system and due to its poor prognosis, there is an increase in the demand for more effective anticancer therapies. Interleukins are potential anticancer agents which can modulate expression of cancer related genes and have therapeutic effects. Interleukin 12 (IL-12) exhibits potent anti-tumor, anti-angiogenic and anti-metastatic activities and represents the ideal candidate for tumor immunotherapy, due to its ability to activate both innate and adaptive immunities. The aim of this study was to evaluate the effect of IL-12 administration on GC tumor growth induced in the cancer xenograft nude mouse model. Tumor development was analyzed weekly and after 8 weeks, the animals were sacrificed for cytokine analysis (IL-4, TNF-alfa, IL-2, INF-gamma, IL-12, IL-10, TGF-beta) by ELISA. The tumor cells in the implanted areas of the animals that developed solid growth of the tumor (anatomopathological analysis was performed). We have also evaluated CASK and miR203 expression, two related cell invasion factors, in the induced tumors after administration of 6 n/kg IL-12. The development of tumor masses was observed in all groups of animals inoculated with HGC-27 neoplastic cells. In animals treated with 6 n/kg IL-12, there was no tumor development confirmed by anatomopathological analysis. Changes in the levels of pro and anti-inflammatory cytokines were also observed. Our results indicated that miR203 expression was elevated while CASK was downregulated. These results suggest that IL-12 treatment repress the tumor growth by induction of miR203 expression which in turn repress CASK expression.

Exploring the potential of two Pseudomonas species to produce vincristine from vinblastine via biotransformation

A biotransformation pair consisting of vinblastine: vincristine present in the Catharanthus roseus plant is of immense pharmacological significance. In this study, we successfully transformed vinblastine into vincristine outside the plant using Pseudomonas aeruginosa 8485 and Pseudomonas fluorescens 2421 and evaluated the antiangiogenic potential of thus produced vincristine through the CAM assay. The toxicity assay showed that both Pseudomonas spp. can tolerate varying concentrations (25–100 µl of 1 mg/ml) of vinblastine. The biotransformation was performed in a liquid nutrient broth medium containing vinblastine (25–100 µl), and Pseudomonas spp. inoculums (50–150 µl) by incubating at 30 °C and 37 °C, respectively for 8 days. The process was optimized for substrate and culture concentrations, pH, temperature, and rotation speed (rpm) for the highest conversion. Analysis using LC–MS/MS confirmed the presence of vincristine as a product of the vinblastine biotransformation by two Pseudomonas spp. P. fluorescens 2421 showed a faster conversion rate with 95% of vinblastine transformed within 24 h than P. aeruginosa 8485, which demonstrated a conversion rate of 92% on the 8th day. From LC–MS/MS analysis, the optimal conditions for the reaction were determined as vinblastine (25 µl), microbial inoculums (150 µl or 200 × 106 and 210 × 106 CFU/ml), pH 7.4, rotation speed of 180 rpm, and temperatures of 30 °C and 37 °C with incubation time of 8 days. The vincristine produced exhibited potent antiangiogenic activity in the CAM assay reducing the thickness and branching of blood vessels in a dose-dependent manner. The study concludes that both Pseudomonas spp. showed promise for vincristine production from vinblastine, without compromising its antiangiogenic properties.

Novel bibenzyl compound Ae exhibits anti-agiogenic activity in HUVECs in vitro and zebrafish in vivo

The inhibition of angiogenesis has been considered as an attractive method for the discovery of potential anti-cancer drugs. Herein, we report our new synthesized bibenzyl compound Ae had potent anti-angiogenic activity(the lowest effective concentration is to 0.62–1.25 μM) in zebrafish in vivo and showed a concentration-dependent inhibition of inter-segmental blood vessels (ISVs) compared to control. Further, Ae exhibited the obvious inhibitory activity of proliferation, migration, invasion and tube formation in HUVEC cells in vitro. Moreover, qRT-PCR analysis revealed that the anti-angiogenic activity of compound Ae is connected with the ang-2, tek in ANGPT-TEK pathway and the kdr, kdrl signaling axle in VEGF-VEGFR pathway. Molecular docking studies revealed that compound Ae had an interaction with the angiopoietin-2 receptor(TEK) and VEGFR2. Additionally, analysis of the ADMET prediction data indicated that compound Ae possessed favorable physicochemical properties, drug-likeness, and synthetic accessibility. In conclusion, compound Ae had remarkable anti-angiogenic activity and could be served as an candidate for cancer therapy.

Ornidazole Inhibits the Angiogenesis and Migration Abilities of Non-small Cell Lung Cancer (NSCLC) via Downregulation of VEGFA/VEGFR2/NRP-1 and PI3K/AKT/mTOR Pathways.

Around the world, non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths among all cancers. Despite advancements in new therapeutic approaches over the past few decades, the five-year survival rate still remains disappointing. The lack of effective anti-angiogenic and anti-migration drugs is the biggest obstacle to the treatment of metastatic lung cancer. Therefore, there is a need to develop new and effective therapeutic compounds targeting anti-angiogenic and anti-migration pathways for the treatment of lung cancer. Ornidazole is a nitroimidazole agent widely used in the treatment of parasitic infections such as trichomonas vaginalis, amebiasis and giardiasis. This study aimed to investigate the anti-proliferative, anti-angiogenic and anti-mitotic activities of the anti-parasitic drug Ornidazole in two human lung cancer cell lines (A549, H1299). We determined the effects of Ornidazole, on cell viability, apoptosis, migration, angiogenesis and metastatic ability against NSCLC in lung cancer cell lines. Its action on the mRNA and protein expression levels of VEGFA, VEGFR2, NRP1, Casp9, Casp3, Bax, Bcl-2, PIK3CA, AKT, MTOR, PTEN and FOX3A was assessed. Furthermore, in this study the effects on cell migration, cell viability and proliferation was evaluated through wound healing, MTT and Crystal violet assays. This study demonstrated that Ornidazole effectively reduces cell viability and migration ability, inhibits angiogenesis and metastatic abilities in NSCLC cells. In conclusion, these results may shed light on the treatment of NSCLC, and we suggest the anti-parasitic drug Ornidazole as a new agent with potential anti-angiogenic and anti-mitotic activity by interfering with the molecular pathways that trigger tumor angiogenesis and migration.

Chemical constituents from a marine medicinal brown alga-derived Xylaria acuta SC1019.

In this study, a marine medicinal brown alga Sargassum cristaefolium-derived fungal strain Xylaria acuta SC1019 was isolated and identified. Column chromatography of the extracts from liquid- and solid-fermented products of the fungal strain was carried out, and led to the isolation of twenty-one compounds. Their structures were characterized by spectroscopic analysis, and the absolute configurations were further established by single X-ray diffraction analysis or modified Mosher's method as nine previously undescribed compounds, namely xylarilactones A-C (1-3), ent-gedebic acid 8-O-α-D-glucopyranoside (4), 5R-hydroxylmethylmellein 11-O-α-D-glucopyranoside (5), ent-hymatoxin E 16-O-α-D-mannopyranoside (6), 19,20-epoxycytochalasin S (7), 19,20-epoxycytochalasin T (8), and (2R)-butylitaconic acid (9), along with twelve known compounds 10-21. All the isolates were subjected to anti-inflammatory and anti-angiogenic assays. Compounds 1, 5, 7, 10, and 17 showed moderate nitric oxide production inhibitory activities in lipopolysaccharide-activated BV-2 microglial cells with IC50 values of 19.55 ± 0.35, 16.10 ± 0.57, 15.20 ± 0.87, 11.76 ± 0.49, and 11.30 ± 0.32 μM, respectively, as compared to curcumin (IC50 = 2.69 ± 0.34 μM) without any significant cytotoxicity. Compounds 7, 8, and 21 displayed potent anti-angiogenic activities by suppressing the growth of human endothelial progenitor cells with IC50 values of 0.44 ± 0.01, 0.47 ± 0.03, and 0.53 ± 0.01 μM, respectively, as compared to sorafenib (IC50 = 5.50 ± 1.50 μM).

Anti-angiogenic and anti-tumour activities of Lignosus rhinocerus (Cooke) Ryvarden water extracts on HCT116 human colorectal carcinoma cells implanted in chick embryos

Ethnopharmacological relevanceThe sclerotium of Lignosus rhinocerus (Cooke) Ryvarden is used by the local communities in Southeast Asia and China to treat cancer, asthma, fever, and other ailments based on traditional knowledge. The sclerotial water extracts were previously reported to exhibit cytotoxic, apoptotic, and immunomodulatory activities – providing a scientific basis for its use in treating cancer; however, there is still a lack of evidence on its potential anti-angiogenic activity. Aim of the studyThis study aimed to investigate the toxicity, anti-angiogenic, and anti-tumour activities of the hot-water and cold-water extracts of L. rhinocerus using HCT116 human colorectal carcinoma cells implanted in the chick chorioallantoic membrane (CAM) model. Materials and methodsThe toxicity of L. rhinocerus extracts towards the chick embryos was determined 24 h post-treatment. The anti-angiogenic activity of the extracts was then investigated at 0.1–10 μg/embryo (6.7–670 μg/mL) at targeted blood vessels. The anti-tumour effect of selected extracts against the HCT116 human colorectal carcinoma cells xenografted onto the chick embryos was also studied. ResultsThe cold-water extracts of L. rhinocerus displayed strong in ovo toxicity (LC50: 1.2–37.7 μg/mL) while the hot-water extracts are non-toxic up to 670 μg/mL. Among the extracts, the hot-water extracts demonstrated the highest anti-angiogenic activity with 44.0 ± 17.7% reduction of capillary diameter (relative to the saline-treated control). Moreover, treatment of the HCT116 cells xenografted onto the chick embryos with the hot-water extracts resulted in smaller tumour size and lower number of blood vessels compared to the saline-treated control. ConclusionsThe hot-water extracts of L. rhinocerus sclerotium demonstrated anti-angiogenic and anti-tumour activities but most of the cold-water extracts at similar concentrations were devoid of that. Our findings provide further scientific validation of the medicinal use of the sclerotium in treating cancer and thus, expanding our knowledge on the possible mechanism of its anti-cancer effect apart from direct cytotoxicity, induction of apoptosis and immunomodulation that have been studied thus far.

Abstract 7144: BR0L075 (SCB01A), a microtubule inhibitor targeting the colchicine binding site, induces immunogenic cell death

Abstract BPR0L075 (also known as SCB01A in phase II clinical trial) is a novel anti-microtubule drug with potent anti-tumor and anti-angiogenic activity in vitro and in vivo. BPR0L075 inhibits tubulin polymerization (microtubule de-stabilizer) by binding to the colchicine-binding site of tubulin. We previously reported that BPR0L075 overcomes paclitaxel (microtubule stabilizer) resistance and induces vascular-disruption in vitro and in vivo. We observed that breast and ovarian cancer cells treated with BPR0L075 in vitro induced key hallmarks of immunogenic cell death (ICD). In both human and murine, ovarian (OVCAR3, ID8) and breast cancer (MDA-MB-231, 4T1) cell lines, treatment with low nanomolar concentration of BPR0L075 significantly decreased the viability of cells evidenced by SRB assay. Using a known ICD inducer mitoxantrone as a positive control, both flow cytometric analysis and immunofluorescence staining assays demonstrated that BPR0L075 treatment led to a time- and dose-dependent translocation of calreticulin, an endoplasmic reticulum chaperone protein, on the plasma membrane of dying cells which sends an “eat me” signal. The BPR0L75 treatment also led to secretion of High Mobility Group Box 1 (HMGB1), a non-histone chromatin-binding nuclear protein, as well as adenosine triphosphate (ATP) from the cell into the extracellular space using ELISA assay. These damage-associated molecular patterns (DAMPs) are known to lead to antigen-presenting cell recruitment, phagocytosis, maturation of dendritic cells, and chemotaxis. The appearance of the ICD biomarkers (calreticulin exposure, HMGB1 and ATP release) supports BPR0L075 as an ICD-inducing antimitotic agent. Further in vivo studies are warranted to delineate the effect of BPR0L075 on immune activation and recruitment of immune cells to the tumor microenvironment. Citation Format: Ayesha Bano, Xinli Liu. BR0L075 (SCB01A), a microtubule inhibitor targeting the colchicine binding site, induces immunogenic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7144.

Impact of atorvastatin and mesenchymal stem cells combined with ivermectin on murine trichinellosis

Trichinellosis is one of the global food-borne parasitic diseases that can cause severe tissue damage. The traditionally used drugs for the treatment of trichinellosis have limited efficacy against the encysted larvae in the muscular phase of the disease. Therefore, this study aimed to evaluate the role of atorvastatin and mesenchymal stem cells combined with ivermectin against different phases of Trichinella in experimentally infected mice. A total of 120 male Swiss albino mice were divided into two major groups (n = 60 of each), intestinal and muscular phases. Then, each group was subdivided into 10 subgroups (n = 6); non-infected control, infected non-treated control, infected ivermectin treated, infected atorvastatin treated, infected mesenchymal stem cells treated, infected combined ivermectin and atorvastatin treated, infected combined mesenchymal stem cells and ivermectin treated, infected combined mesenchymal stem cells and atorvastatin treated, infected combined mesenchymal stem cells and a full dose of (ivermectin and atorvastatin) treated, and infected combined mesenchymal stem cells and half dose of (ivermectin and atorvastatin) treated. Mice were sacrificed at days 5 and 35 post-infection for the intestinal and muscular phases, respectively. The assessment was performed through many parameters, including counting the adult intestinal worms and muscular encysted larvae, besides histopathological examination of the underlying tissues. Moreover, a biochemical assay for the inflammatory and oxidative stress marker levels was conducted. In addition, levels of immunohistochemical CD31 and VEGF gene expression as markers of angiogenesis during the muscular phase were investigated. The combined mesenchymal stem cells and atorvastatin added to ivermectin showed the highest significant reduction in adult worms and encysted larvae counts, the most noticeable improvement of the histopathological changes, the most potent anti-inflammatory (lowest level of IL-17) and anti-angiogenic (lowest expression of CD31 and VEGF) activities, and also revealed the highly effective one to relieve the oxidative stress (lowest level of SOD, GSH, and lipid peroxidase enzymes). These observed outcomes indicate that adding mesenchymal stem cells and atorvastatin to ivermectin synergistically potentiates its therapeutic efficacy and provides a promising candidate against trichinellosis.

A 1, 4-benzoquinone derivative isolated from Ardisia crispa (Thunb.) A. DC. root suppresses angiogenesis via its angiogenic signaling cascades

The root hexane extract of Ardisia crispa (ACRH), which belongs to the Primulaceae family, has been reported to possess anti-inflammatory, chemopreventive, anti-arthritic, and antiangiogenic activities. In this study, we isolated a p-benzoquinone derivative, 2-methoxy-6-undecyl-1,4-benzoquinone (AC2), from ACRH and investigated its potential antiangiogenic activity in human umbilical vein endothelial cells (HUVECs) and zebrafish embryo models. Prior to this study, AC2 was characterized using 1H NMR spectroscopy and MS. AC2 significantly suppressed HUVEC proliferation in a time-independent manner, with an IC50 value of 1.35 ± 0.05, 1.15 ± 0.02, and 1.00 ± 0.01 µg/mL at 24, 48, and 72 h, respectively. AC2 also induced apoptosis in HUVECs and significantly suppressed their migration, invasion, and tube formation in a concentration-dependent manner. Additionally, AC2 significantly attenuated most of the analyzed protein markers, including pro-MMP-2, VEGF-C, VEGF-D, angiopoietin-2, endothelin-1, fibroblast growth factor (FGF)-1, FGF-2, follistatin, heparin-binding epidermal growth factor-like growth factor (HB-EGF), and hepatocyte growth factor (HGF) at all tested concentrations. Furthermore, AC2 significantly inhibited zebrafish embryo intersegmental vessels (ISVs), confirming its antiangiogenic role. In conclusion, AC2 exhibits a potential anti-angiogenic effect by suppressing several proangiogenic and growth factors. Further studies are needed to investigate their effects on other excessive angiogenic diseases.

2-Nucleobase-substituted 4,6-Diaminotriazine Analogs: Synthesis and Anti-cancer Activity in 5-Fluorouracil-sensitive and Resistant Colorectal Cancer Cells.

Cancer continues to be the second leading cause of death worldwide, with colorectal cancer (CRC) being the third most common type. Despite significant advances in cancer therapies, the current treatment of CRC remains suboptimal. In addition, the effectiveness of available chemotherapeutic drugs such as 5-Fluorouracil (5-FU) is limited by CRC-acquired resistance. In this study, we provide innovative approaches employed in synthesizing four novel nucleobase analogs. Equally, we describe the effects of these compounds on proliferation, migration, aggregation, and adhesion of 5-FU-sensitive (HCT116) and -resistant (5-FU-R-HCT116) human CRC cells. In either cell type, our synthesized novel analogs significantly inhibited cell viability in a concentration- and time-dependent manner. This highlights the higher potency of these novel analogs. In addition, these compounds attenuated migration and adhesion of both cell types while they promoted homotypic cell-cell interaction. These changes were reflected by the downregulation of matrix metalloproteases (MMP-2 and MMP-9). Furthermore, our analogs exhibited potent anti-angiogenic activity in vivo. These novel nucleobase analogs reduced the level of secreted vascular endothelial growth factor (VEGF) and nitric oxide (NO) production in both 5-FU-sensitive and -resistant CRC cells. Taken together, our data highlight the potential chemotherapeutic properties of our novel analogs against CRC, including the 5-FU-resistant form.

Inhibition of tumor-specific angiogenesis by AS1411 aptamer functionalized Withaferin A loaded PEGylated nanoliposomes by targeting nucleolin

Angiogenesis is a vital process for tumor growth and metastasis. Inhibition of angiogenesis is a promising strategy in cancer treatment. In this study, we analyzed the anti-angiogenic activity of AS1411 functionalized Withaferin A encapsulated PEGylated nanoliposomes (ALW) using both in vitro and in vivo models. AS1411 aptamer functionalized nanoliposomes are an efficient drug delivery system for carrying chemotherapeutic agents to target cancer cells, and Withaferin A (WA) is a steroidal lactone known for potent anti-angiogenic activity. ALW showed significant inhibition in the migration and tube formation of endothelial cells, which are critical events in angiogenesis. In vivo angiogenesis study using ALW showed remarkable inhibition of tumor-directed capillary formation by altered serum cytokines, VEGF, GM-CSF, and NO levels. ALW treatment downregulated the gene expression of Matrix metalloproteinase (MMP)-2, MMP-9, VEGF, NF-kB and upregulated the expression of tissue inhibitor of metalloproteinase (TIMP)-1. Our results demonstrate that ALW inhibits tumor-specific angiogenesis by gene expression of NF-κB, VEGF, MMP-2, and MMP-9. The present study shows that using ALW can offer an attractive strategy for inhibiting tumor angiogenesis.

Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation

The colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum in vitro antitumour activity. In this study, structure based rational design and systematic structural optimisation were performed to obtain analogues C1∼J2 bearing diverse substituents and scaffolds. Among them, analogue G13 bearing a hydroxymethyl group displayed good tubulin polymerisation inhibitory activity (IC50 = 13.5 μM) and potent antiproliferative activity (IC50 values: 0.65 μM∼0.90 μM). G13 potently inhibited the migration and invasion of MDA-MB-231 cells, and displayed potent antiangiogenic activity. It efficiently increased intracellular ROS level and decreased MMP in cancer cells, and obviously induced the fragmentation and disassembly of the microtubules network. More importantly, G13 exhibited good in vivo antitumour efficacy in MDA-MB-231 xenograft model (TGI = 38.2%; i.p., 30 mg/kg).

Innovative challenge for the inhibition of hepatocellular carcinoma progression by combined targeting of HSP90 and STAT3/HIF-1α signaling

Hepatocellular carcinoma (HCC) is the third foremost cause of cancer-related deaths. HCC has a very bad prognosis because it is asymptomatic in the early stages, resulting in a late diagnosis, and it is highly resistant to conventional chemotherapy. Such chemotherapies have been proven disappointing because they provide extremely low survival benefits. This study discloses that the STAT3/HIF-1α is an auspicious therapeutic attack site for conceivable repression of HCC development. A site that can be targeted by simultaneous administration of a STAT3 inhibitor in the context of HSP90 inhibition. 17-DMAG binds to HSP90 and constrains its function, resulting in the degradation of HSP90 client proteins HIF-1α and STAT3. Hypoxia recruits STAT3/HIF-1α complex within the VEGF promoter. Additionally, it was acknowledged that STAT3 is an essential mediator of VEGF transcription by direct binding to its promoter. Furthermore, it induces HIF-1α stability and enhances its transcriptional activity. Herein, we revealed that the combination therapy using 17-DMAG and nifuroxazide, a STAT3 inhibitor, repressed the diethylnitrosamine-induced alterations in the structure of the liver. This effect was mediated via decreasing the levels of the HSP90 client proteins HIF-1α and pSTAT3 resulting in the suppression of the STAT3/HIF-1α complex transcriptional activity. To conclude, 17-DMAG/NFXZD combination therapy-induced disruption in the STAT3/HIF-1α loop led to a potential antiangiogenic activity and showed apoptotic potential by inhibiting autophagy and inducing ROS/apoptosis signaling. Additionally, this combination therapy exhibited promising survival prolongation in mice with HCC. Consequently, the use of 17-DMAG/NFXZD renders an inspirational perspective in managing HCC. However, further investigations are compulsory.

A copper complex that combats triple negative breast cancer by restraining angiogenesis.

Angiogenesis and metastasis are major factors affecting the growth and invasion of triple negative breast cancer (TNBC). A phenanthroline copper(II) complex CPT8 modified with an alkyl chain-linked triphenylphosphonium group showed potent antiproliferative activity against a series of cancer cells including TNBC MDA-MB-231 cells. CPT8 induced mitophagy through activation of PINK1/Parkin and BNIP3 pathways in cancer cells due to damage to mitochondria. More importantly, CPT8 reduced the tube formation ability of human umbilical vein endothelial cells (HUVEC) through downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). The anti-angiogenic potential of CPT8 was confirmed by decreased vascular endothelial growth factor (VEGF) and CD34 expression in HUVEC. Moreover, CPT8 suppressed the expression of vascular endothelial cadherin and matrix metalloproteinases MMP2 and MMP9, leading to the inhibition of vasculogenic mimicry formation. CPT8 also weakened the metastatic potential of MDA-MB-231 cells. Downregulation of Ki67 and CD34 expression indicates that CPT8 suppressed tumor proliferation and vascularization in vivo, thus providing a unique metal drug candidate for the treatment of TNBC.

Structure-activity relationship of triterpenoid saponins: Biological properties and commercial applicabilities

Saponins are plant-derived non-ionic surfactants and widely applied in many products, such as cosmetics, cleansers, medicines, vaccine, as additives by therapeutic properties and chemical characteristics theirs. These substances are of growing interest for drug research as they’re active constituents of several folk medicines, in addition to comprising an important class of medicinal chemistry. Triterpenoid saponins are secondary metabolites, these’re largely distributed in plant species and they’re characterized as one of the active principles of these. These saponins have potent anti-viral, adjuvant, hemolytic, cytotoxic and anti-angiogenic activities that are relationship with the presence of characteristics chemical moiety. In this work was summarized the studies found in the scientific literature on the therapeutic properties of triterpenoid saponins, as well as commercial applicability theirs. Recent works have suggested some triterpenoid saponins like candidates for treatment of patients with COVID-19.

Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis

Aminopeptidase N (APN) was closely associated with cancer invasion, metastasis, and angiogenesis. Therefore, APN inhibitors have attracted more and more attention of scientists as antitumor agents. In the current study, we designed, synthesized, and evaluated one new series of pyrazoline-based hydroxamate derivatives as APN inhibitors. Moreover, the structure-activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound 14o with R1 = CH3, showed the best capacity for inhibiting APN with an IC50 value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound 14o possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound 14o exhibited much better capacity for inhibiting the micro-vessel growth relative to bestatin in the rat thoracic aorta ring model. Additionally, the putative interactions of 14o with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His297, Glu298 and His301. Meanwhile, the terminal phenyl group and another phenyl group of 14o interacted with S2' and S1 pockets via hydrophobic effects, respectively.

Pharmacokinetics of fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (NP751), a novel anticancer thyrointegrin αvβ3 antagonist.

We have recently reported on the development of fb-PMT (NP751), a conjugate of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol 36. It exhibited high affinity for thyrointegrin αvβ3 receptor and potent anti-angiogenic and anticancer activity in vivo. The objective of the current study is to determine the pharmacokinetics (PK) of fb-PMT in experimental animals, such as mice, rats, and monkeys. NP751 was quantified using a propylene diamine-modified tetraiodothyroacetic acid (DAT) as an internal standard. The limit of quantification (LOQ) for fb-PMT was 1.5ng/μL and the recovery efficiency was 93.9% with the developed method. The peak plasma concentration (Cmax) and the area under the curve (AUC) results at different doses in mice, rats and monkeys suggest that pharmacokinetics of NP751 is dose-dependent within the dose ranges administered. Results indicate that NP751 has comparable PK parameters that provides enough exposure as a molecularly tumor targeted molecule in multiple species and is a promising anticancer therapeutic.

Nutraceutical-Based Nanoformulations for Breast and Ovarian Cancer Treatment.

Different strategies have been investigated for a more satisfactory treatment of advanced breast cancer, including the adjuvant use of omega-3 polyunsaturated fatty acids (PUFAs). These nutritional compounds have been shown to possess potent anti-inflammatory and antiangiogenic activities, the capacity to affect transduction pathways/receptors involved in cell growth and to reprogram tumor microenvironment. Omega-3 PUFA-containing nanoformulations designed for drug delivery in breast cancer were shown to potentiate the effects of enclosed drugs, enhance drug delivery to target sites, and minimize drug-induced side effects. We have critically analyzed here the results of the most recent studies investigating the effects of omega-3 PUFA-containing nanoformulations in breast cancer. The anti-neoplastic efficacy of omega-3 PUFAs has also been convincingly demonstrated by using preclinical in vivo models of ovarian cancer. The results obtained are critically analyzed here and seem to provide a sufficient rationale to move to still lacking interventional clinical trials, as well as to evaluate possible advantages of enclosing omega-3 PUFAs to drug-delivery nanosystems for ovarian cancer. Future perspectives in this area are also provided.

Brassinin Promotes the Degradation of Tie2 and FGFR1 in Endothelial Cells and Inhibits Triple-Negative Breast Cancer Angiogenesis

Simple SummaryBrassinin is a natural compound enriched in several commonly consumed vegetables, such as broccoli and cabbages. It shows potent anti-cancer activity against several cancers. However, its effects on triple-negative breast cancer (TNBC), an aggressive subtype with limited treatment options, remain elusive so far. Therefore, we investigated the effects of brassinin on TNBC angiogenesis and growth. Our results demonstrate that brassinin inhibits TNBC growth preferentially through inhibiting the angiogenic activity of endothelial cells (ECs). Additional in-vitro analyses revealed that this effect may be mediated by brassinin-stimulated degradation of two pivotal angiogenesis-related receptors in ECs: Tie2 and fibroblast growth factor receptor 1. These findings provide novel insights into the cellular and molecular mechanisms underlying the anti-cancer activity of brassinin and indicate that this phytochemical may be a promising lead compound or drug candidate for TNBC treatment.Brassinin, a phytoalexin derived from cruciferous vegetables, has been reported to exhibit anti-cancer activity in multiple cancer types. However, its effects on triple-negative breast cancer (TNBC) development and the underlying mechanisms have not been elucidated so far. In this study, we demonstrated in vitro that brassinin preferentially reduces the viability of endothelial cells (ECs) when compared to other cell types of the tumor microenvironment, including TNBC cells, pericytes, and fibroblasts. Moreover, brassinin at non-cytotoxic doses significantly suppressed the proliferation, migration, tube formation, and spheroid sprouting of ECs. It also efficiently inhibited angiogenesis in an ex-vivo aortic ring assay and an in-vivo Matrigel plug assay. Daily intraperitoneal injection of brassinin significantly reduced tumor size, microvessel density, as well as the perfusion of tumor microvessels in a dorsal skinfold chamber model of TNBC. Mechanistic analyses showed that brassinin selectively stimulates the degradation of Tie2 and fibroblast growth factor receptor 1 in ECs, leading to the down-regulation of the AKT and extracellular signal-regulated kinase pathways. These findings demonstrate a preferential and potent anti-angiogenic activity of brassinin, which may be the main mechanism of its anti-tumor action. Accordingly, this phytochemical represents a promising candidate for the future anti-angiogenic treatment of TNBC.