Antineoplastic Activity Research Articles

AGITG ASCEND: Randomised, double-blind phase II study of certepetide or placebo added to gemcitabine plus nab-paclitaxel in patients with untreated metastatic pancreatic ductal adenocarcinoma: Initial results.

728 Background: Gemcitabine (GEM) plus nab-paclitaxel (NAB-PAC) is a standard first-line chemotherapy regimen for advanced/metastatic pancreatic ductal adenocarcinoma (PDAC), with median Progression Free Survival (mPFS) and Overall Survival (mOS) of 5.5 & 8.7 in the MPACT trial and 5.6 & 9.2 months (mo) in the NAPOLI 3 trial, respectively. Certepetide (formerly LSTA1 or CEND-1) is a novel cyclic peptide that improves targeted penetration of co-administered drugs into tumor and stroma, leading to potentially increased anti-neoplastic activity. ASCEND is a randomized phase II trial designed to investigate the impact of adding certepetide to GEM/NAB-PAC. (NCT05042128). Methods: Eligible participants (pts) with histologically confirmed advanced PDAC and ECOG 0-1 were randomized 2:1 to receive GEM/NAB-PAC plus certepetide (3.2 mg/kg) or placebo (PLA) on days 1, 8, & 15 of a 28-day cycle. Stratification was by age (<65/≥65 years), ECOG (0/1), presence of liver metastasis (Y/N) and trial site. The primary objective was to determine the effect of adding certepetide to GEM/NAB-PAC on PFS. Objective tumor response rate (OTRR), safety and OS were secondary objectives. This non-comparative phase II design targeted a PFS increase of 17% at 6 mo from 47% to 63%. A sample size of 65 patients in the certepetide arm was expected to have 80% power, with 95% confidence to exclude an uninteresting 6-mo PFS rate of 47%. Results: 95 pts (66 certepetide, 29 PLA) were enrolled between May 2022 to December 2023. 6-mo PFS in the certepetide and PLA groups was 49.0% (95% CI 36.4%, 60.5%) and 40.8 (95% CI 22.6%, 58.3%) respectively, with mPFS of 5.5 mo in both groups. mOS was 12.42 mo for the certepetide and 9.72 mo for the PLA. An OTRR of 38.3% (certepetide) and 26.9% (PLA) was observed. Of note, 4 complete responses were observed in the certepetide group vs. 0 in PLA group. In subjects with ECOG 0, 6 mo PFS was 68.1% (95% CI 48.7%, 81.4%) in the certepetide compared to 36.4% (95% CI 11.2%, 62.7%) in the PLA. Grade ≥3 toxicities were similar in both groups at 16% (certepetide) and 15% (PLA). Conclusions: The addition of certepetide is safe and despite showing no improvement in 6-mo PFS, a possible signal of benefit in OS and OTRR, including the 4 complete responses was observed, warranting further investigation. A further cohort of the ASCEND study evaluating the addition of a second dose of certepetide is ongoing. Clinical trial information: NCT05042128 .

Unlocking the potential of Calculus bovis: A breakthrough in liver cancer treatment via Wnt/β-catenin pathway modulation.

Liver cancer remains a significant global health challenge, characterized by high incidence and mortality rates. Despite advancements in medical treatments, the prognosis for liver cancer patients remains poor, highlighting the urgent need for novel therapeutic approaches. Traditional Chinese medicine (TCM), particularly Calculus bovis (CB), has shown promise in addressing this need due to its multi-target therapeutic mechanisms. CB refers to natural or synthetic gallstones, traditionally sourced from cattle, and used in TCM for their anti-inflammatory, detoxifying, and therapeutic properties. In modern practice, synthetic CB is often utilized to ensure consistent supply and safety. This article aims to discuss the findings of Huang et al, who investigated the anti-liver cancer properties of CB, focusing on its ability to inhibit M2 tumor-associated macrophage (TAM) polarization via modulation of the Wnt/β-catenin pathway. Huang et al employed a comprehensive approach integrating chemical analysis, animal model testing, and advanced bioinformatics. They identified active components of CB using UPLC-Q-TOF-MS, evaluated its anti-neoplastic effects in a nude mouse model, and elucidated the underlying mechanisms through network pharmacology, transcriptomics, and molecular docking studies. The study demonstrated that CB significantly inhibited liver tumor growth in vivo, as evidenced by reduced tumor size and weight in treated mice. Histological analyses confirmed signs of tumor regression. CB was found to modulate the tumor microenvironment by inhibiting the polarization of M2 phenotype-TAMs, as shown by reduced expression of M2 markers and downregulation of mRNA levels of C-C motif chemokine 22, arginase-1, transforming growth factor-beta 2, and interleukin-10. The study further revealed that CB's antineoplastic activity involved the downregulation of Wnt5B and β-catenin and upregulation of Axin2, thus inhibiting the Wnt/β-catenin signaling pathway. These findings highlight the therapeutic potential of CB in liver cancer treatment through its modulation of the Wnt/β-catenin pathway and suppression of M2 phenotype-TAM polarization. This study underscores the value of integrating TCM with modern therapeutic strategies to develop novel effective treatments for liver cancer.

Identification of Novel Progesterone Receptor (PR) Inhibitors (Homo sapiens) from Metabolites of Biotransformation Fungal: A Bioinformatics Approach

Background/Objectives: Steroids have demonstrated selective cytotoxic properties against tumor cells. The pro-gesterone receptor (PR) plays a vital role in the proliferation, cell differentiation, and maintenance of female reproductive tissue, and its malfunction can lead to breast cancer. The use of the biocatalytic method by filamentous fungi has sparked interest in the obtained of steroids due to the advantages of the process. Methods: Pharmacokinetic and toxicological properties (rat and mouse), molecular docking simulation studies, and prediction of the spectrum of biological activity were performed to select molecules with the potential for PR inhibition, from 155 biotransformed products of the progesterone. Subsequently, the chemical structures were subjected to an evaluation of their pharmacokinetic and toxicological properties and, with the application of ADMET filters. Results: Androstenedione, 17α-hydroxyprogesterone, and dihydrotestosterone, obtained by the process of biotransformation of PR by different filamentous fungi, showed good pharmacokinetic profiles and low toxicity compared to the control groups. The in-silico data associated with molecular docking studies revealed the best binding affinity and similarity in the interactions of these molecules against the human progesterone receptor target. Thus, the results of biological activity spectrum prediction highlight the great potential to investigate the role of molecular descriptors in the attribution of anti-cancer activities. Conclusions: The biocatalytic process, by filamentous fungi, can provide important molecules as a product of progesterone biotransformation, such as androstenedione, 17α-hydroxyprogesterone, and dihydrotestosterone. In this study we showed that these molecules have good pharmacokinetic profiles and low toxicity for antineoplastic activity (breast cancer).

Plant-derived compounds with antineoplastic activity: a literature review

Plant-derived compounds with antineoplastic activity: a literature review

Synthesis and Biological Evaluation of a New Biphenyl-Based Organogold(III) Complex with In Vitro and In Vivo Anticancer Activity.

Despite recent advances in cancer treatment, there is still a need for novel compounds with antineoplastic activity. Among 11 biphenyl-based organogold(III) N-heterocyclic carbene (NHC) (BGC) complexes of general formula [(C^C)Au(NHC-pyr)X], where (C^C) = 4,4'-ditertbutylbiphenyl, X = Cl or phenylacetylide, and (NHC-pyr) is a pyridyl-substituted NHC ligand, the complex BGC4 bearing a 4-CF3-pyridyl substituent and a chloride ligand showed promising antineoplastic activity on the triple negative breast cancer cell line. BGC4 was able to induce cell apoptosis but had no effect on the cell cycle. In vivo, BGC4 reduced the tumor growth rate by increasing the necrosis area and decreasing the mitotic activity. Repeated injections of BGC4 did not induce common side effects. The present investigation shows that BGC4 is a promising antineoplastic candidate. Its potential as a future chemotherapy for the treatment of cancer will be strengthened by evaluating its efficacy in combined treatment with current chemotherapy.

In vitro Metabolism and Cytotoxicity of Parthenolide: The Complete Identification of the Major Oxidative Product and the Evaluation of Trypanocidal and Leishmanicidal Activities

Parthenolide (PTN) is a secondary metabolite of the plant Tanacetum parthenium (L.) Schulz Bip. and is considered the chemical marker of this species. This sesquiterpene lactone (germacrene skeleton) has been described as responsible for the biological activity of the leaf extract. In addition, several studies in the literature have demonstrated its antiparasitic and antineoplastic activity. However, there is a need for knowledge of other safety parameters, such as pharmacokinetic, pharmacodynamic and toxicity evaluations. Therefore, in this investigation, the in vitro metabolism of parthenolide was performed with rat liver microsomes and biomimetic metabolism (such as cytochrome P-450 system) using organometallic catalysts. The biomimetic procedure was validated since the major compound of biomimetic oxidative reaction with meta-chloroperbenzoic acid catalyzed by metalloporphyrin 5,10,15,20-tetrakis(pentafluorophenyl)-porphyrin iron(III) chloride was also observed with rat liver microsomes. Previous chemoenzymatic synthesis studies of PTN afforded the same epoxide formation, this major oxidative compound was isolated and fully characterized as (1R,10R)-epoxyparthenolide based on experimental and theoretical calculations of infrared (IR) and vibrational circular dichroism (VCD) data at the B3PW91/6-311G. Furthermore, for the first time, this metabolite was evaluated for trypanocidal and leishmanicidal activity. The mean inhibitory concentration (IC50) values were lower for PTN than its metabolite and showed significant cytotoxic effects for both parasites. This finding holds promise for addressing neglected diseases.

In Silico Investigation and MD Simulation Approaches of Newly Designed Quercetin–Imidazole Analogs for Anticancer and Antifungal Efficacy

AbstractMolecules with potency and low toxicity are the leading army in the battlefield of multidrug resistance. Quercetin is found in abundance in the nature as a potent flavonoid and bears the tag of flavonoid paradox due to the poor bioavailability, however, it still possess distinct systemic actions, and this marks curiosity in the research field. The present study elaborates targeted in silico and simulation approaches of newly designed quercetin analogs toward their anticancer and antifungal properties by screening against human epidermal growth factor receptor and lanosterol C14‐alpha demethylase receptors. The molecules were investigated pharmacokinetically via drug‐likeness, toxicity prediction (lethal dose, LD50), PASS prediction, molecular docking, molecular dynamics simulation, and their quantum mechanics have been measured using molecular orbital calculations through highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) calculations. The prediction from Pa > Pi scores displayed its potential for squalene epoxide inhibitors, antimycobacterial, and antineoplastic activities and also showed prospectively better molecular docking scores against the selected targeted enzymes. Among the series, QIz II stood out as a compelling inhibitor; showcasing highest binding affinity with fungal protein by impressive docking score of −10.7 kcal/mol. Compound QIz XX demonstrated the highest binding affinity of −9.31 kcal/mol with the anticancer protein.

Methanolic Extract of Morchella esculenta (Ascomycota) Prevents Chemotherapy-Related Cardiotoxicity in Tumor-Bearing Mice

The quest for bioactives that confer protection against chemotherapy induced cardio toxicity is a front-line area of cardio oncology research. Species of genus <i>Morchella</i> have been used in traditional medicine to treat asthma, wound healing, cough, cold, indigestion, excessive phlegm and breathlessness. <i>M. esculenta</i>, commonly known as guchhi in India is a highly prized culinary morel mushroom. Recent studies carried out in our laboratory have demonstrated significant cardioprotective effect of <i>M. esculenta</i> against doxorubicin (DOX)-induced cardiotoxicity. Since bioactive extracts of morel mushrooms were found to possess profound antioxidant activity, the possible interference of these extracts with antineoplastic activity of chemotherapy drugs is often surmised. The current study was undertaken to evaluate the effect of two anticancer drugs, DOX and cyclophosphamide (CP) on solid tumor-bearing mice treated with bioactive extract of <i>M. esculenta</i>. Solid tumor was induced by subcutaneous injection of Dalton's lymphoma ascites (DLA) cells on the right hind limbs of Swiss albino mice. Animals were administered with various concentrations of methanol extract (ME) of <i>M. esculenta</i> following tumor induction. Tumor growth (volume and mass) was measured for four weeks after tumor induction. Cardioprotective effect of methanolic extract was assessed by determining cardiac injury markers levels in serum, antioxidant status in myocardium and histopathology of heart tissue. The results showed significant cardioprotective effect of ME of <i>M. esculenta </i>on tumor-bearing mice. The findings also suggest that ME of <i>M. esculenta</i> did not delimit the therapeutic effect of DOX and CP despite its profound antioxidant activity.

Calculus bovis hijacks the tumor microenvironment in liver cancer cells in a multifaceted approach: A falling row of dominoes.

Calculus bovis (C. bovis) is widely used in traditional Chinese medicine due to its anti-tumor effects. C. bovis shifts liver cancer tumor microenvironment towards regression by hindering tumor-associated macrophages polarization. Huang et al have demonstrated in their study that C. bovis inhibits M2-tumour-associated macrophages (TAM) polarization by halting the Wnt/β-catenin pathway. The mechanism of action by which C. bovis exerts its anti-tumor effects is multifaceted and includes network pharmacology, transcriptomics and molecular docking. In vitro assays demonstrated that C. bovis-containing serum inhibited M2-TAMs polarization in human hepatocellular carcinomas cells. C. bovis was found to have 22 active components of which 11 were detected in the bloodstream. The anti-neoplastic activity of C. bovis lies in suppressing M2-TAM polarization by modulation of the Wnt/B-catenin pathway. In vitro and in vivo experiments have shown that C. bovis suppresses M2-TAM polarization and halts the Wnt signaling pathway. The inhibitory effect of C. bovis on M2-TAM was reversed by SKL2001, a Wnt agonist, which highlights C. bovis's selectivity and specificity. C. bovis inhibits M2-TAM polarization by modulating the Wnt/ β-catenin pathway, thus impeding liver cancer growth. Owing to the "cross-talk" between transforming growth factor-β (TGF-β) signaling pathways, this paper highlights the potential significance of C. bovis in controlling the tumor microenvironment not only through hindering the polarization of M2-TAMs via the Wnt signaling pathway, but also by downregulating TGF-β. Therefore, C. bovis serves as an igniter to fuel a cascade of signaling events that culminates in the regression of the tumor microenvironment by compromising oncogenesis and angiogenesis. TGF-β is also known for its pro-fibrotic properties. Therefore, C. bovis may play a pivotal role in treating liver fibrosis by downregulating TGF-β, thus hindering oncogenesis, angiogenesis and liver fibrosis. Hence, the "domino effect".

Production of L-Asparaginase using Soil Isolate of Cladosporium sp. and Evaluation of its Antitumor and Antioxidant Activities

The enzyme L-asparaginase is given prime attention in healthcare settings owing to its significant therapeutic applications in oncology. The present study isolated five different species of fungi belonging to the genera Aspergillus (23.8 and 9.5%), Cladosporium (19%), Fusarium (14.3%) and Penicillium (19%) from soil samples. Screening on Czapek Dox’s medium indicated that the isolate Cladosporium sp. ASP4 exhibit higher potential of synthesizing L-asparaginase than other fungi by means of causing a halo zone measuring 22.3 mm dia. Fermentation of standard medium ingredients along with the solid substrate soya bean meal by the potential fungal isolate resulted in the production of 20.53 IU/mL of L-asparaginase. Optimization studies deciphered the carbon source sucrose, supplementary nitrogen ammonium nitrate, pH ≥8.0 and the temperature 50oC as favorable process parameters for the enzyme production. Purified L-asparaginase of the present study demonstrated moderate antineoplastic activity against the A549 lung cancer cells with the IC50 values of ≥50 IU/mL. The enzyme displayed better antioxidant property compared to those of previous studies by way of scavenging the radicals with the SC50 values of ≥250 mg/mL. These findings encourage carrying out further elaborate studies for prospective biotechnological and pharmaceutical applications of the purified enzyme.

Pathomorphological analysis of salinomycin and nanodiamonds efficacy on Lewis lung carcinoma in mice

Relevance. The search for new antitumor drugs and their selective delivery directly to the tumor site is an important task of modern oncology. For these purposes, currently, the use of various nanoparticles as carriers of medicinal substances is of great importance. The pathomorphological features of tumor cells under the action of salinomycin and nanodiamonds have not been studied enough. The aim of the work was to study the pathomorphological features of the tumor in mice with transplanted Lewis lung carcinoma, who were treated with the ionoform antibiotic salinomycin and a combination of salinomycin with nanodiamonds. Material and methods. 20 mice were divided into 4 groups. 1 – control group; 2 – mice received salinomycin; 3 – salinomycin and nanodiamonds; 4 – nanodiamonds. A morphometric study of histological and immunohistochemical tumor preparations stained for PCNA was carried out. Results. Salinomycin is established to have an antineoplastic action. The use of nanodiamonds did not significantly affect the morphofunctional characteristics of Lewis lung carcinoma and did not change the antitumor activity of salinomycin. Conclusion. Salinomycin has an antitumor effect and requires further research.

Effect of ozonation on the phytochemicals of black seed oil and its anti-microbial, anti-oxidant, anti-inflammatory, and anti-neoplastic activities in vitro

Black seed has been applied for several decades to cure an extensive variety of illnesses and ailments. In this report, the chemical profile of both crude and ozonized black seed oil was assessed after the oil was exposed to 0 to 5 L/minute of ozone for four hours. The in vitro effects of black seed oil following being exposed to ozone including antimicrobial properties versus Bacillus cereus (ATCC11778), Staphylococcus aureus (ATCC6538), Escherichia coli (ATCC8739), Salmonella typhi (ATCC 6539), and Klebsiella pneumoniae (ATCC13883), Candida albicans (ATCC10221), and Aspergillus niger (ATCC16888). Besides, antioxidant effects, anti-inflammatory capacity, and antineoplastic function versus HCT cells were assessed. The chemical profile of ozonized black seed oil showed elevation of essential molecules of oil as well as presence of some characteristic molecules to both forms of oil. Besides, it could be noticed that exposing of oil to ozone improves its antimicrobial activity towards all tested microbes except for C. albicans. Both forms of oil showed no activity towards A. niger. Black seed oil exposed to ozone showed a promising antioxidant capacity with IC50 of 2.93 ± 0.2 µg/ml. A dramatic improvement in anti-inflammatory impact of ozonized oil as well as its antitumor capacity towards HCT cells could be seen in the laboratory outcomes. The current findings point to a novel method for enhancing some of the in vitro medicinal uses of black seed oil by exposing it to ozone.

Theoretical-Cheminformatic Study of Four Indolylphytoquinones, Prospective Anticancer Candidates.

Background/Objectives: Breast cancer is a disease with a high mortality rate worldwide; consequently, urgent achievements are required to design new greener drugs, leaving natural products and their derivatives as good options. A constant antineoplastic effect has been observed when the phytoproduct contains an indole fragment. Methods: Therefore, the objective of this work was to carry out a thoughtful computational study to perform an appropriate evaluation of four novel molecules of the class of the 3-indolylquinones as phytodrug candidates for antineoplastic activity: thymoquinone (TQ), 2,6-dimethoxy-1,4-benzoquinone (DMQ), 2,3-dimethoxy-5-methyl-1,4-benzoquinone (DMMQ), and 2,5-dihydroxy-1,4-benzoquinone (DHQ). It is important to highlight that the obtained computational results of the target compounds were compared-correlated with the theoretical and experimental literature data previously reported of several indolylquinones: indolylperezone, indolylisoperezone, indolylmenadione, and indolylplumbagin (IE-IH, respectively). Results: The results revealed that the studied structures possibly presented antineoplastic activity, in addition to the fact that the reactivity parameters showed that two of the evaluated compounds have the option to present IC50 values lower than or similar to 25 mg/mL, activity like that of indolylisoperezone; moreover, they show molecular coupling to PARP-1. Finally, the prediction of the calculated physicochemical parameters coincides with the Lipinski and Veber rules, indicating that the adsorption, metabolism, and toxicity parameters are acceptable for the studied compounds, obtaining high drug score values. Conclusions: Finally, a comparison between the proposed molecules and others previously synthesized was appropriately performed, establishing that the synthesis of the studied compounds and the determination of their pharmacological properties in an experimental manner are of interest.

Construction of Isochromanones via Hemin-Catalyzed Phenol-Enamine Oxidative Annulation.

We have developed a hemin-catalyzed biomimetic oxidative annulation of 2,3-dihydroxybenzoic acid with an array of cyclic enamines to form isochromanones in good to excellent yields and high regioselectivity. This formal [4+2] cycloaddition protocol showed high efficiency and remarkable functional group tolerance. Mechanistic studies indicate the involvement of a single-electron oxidation pathway. Preliminary biological investigations showed that isochromanones 3ag and 3ca exhibited antineoplastic activities against MCF-7 cell lines with IC50 values of 25.21 and 29.09 μM, respectively.

Characterization of Serratia marcescens (OK482790)’ prodigiosin along with in vitro and in silico validation for its medicinal bioactivities

BackgroundMicrobial prodigiosin pigment has been proposed as a promising biomolecule having an antibacterial, immunosuppressive, antimalarial, antineoplastic, and anticancer activities. The good outcome originates from getting natural pigment, which has many medical applications.ResultsIn this investigation, prodigiosin (PG) was extracted, characterized by UV-visible spectroscopy, thin-layer chromatography, mass spectroscopy, Fourier-transform infrared spectroscopy, and tested in various medical applications as an antibacterial, antioxidant, antibiofilm, anticancer, and wound healing agent at different concentrations. Antibacterial activity of PG pigment was shown against both Gram-positive and Gram-negative bacterial strains. Enterococcus faecalis was the most severely impacted, with minimum inhibitory value of 3.9 µg/mL. The formed biofilm by Pseudomonas aeruginosa was suppressed by 58–2.50% at prodigiosin doses ranging from 1000 to 31.25 µg/mL, respectively. The half-maximal inhibitory concentration (IC50) of 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) free radical was 74.18 ± 23.77 µg/mL. At 100 µg/mL concentration, OK482790 prodigiosin had no harmful effect on normal skin cells and exhibited mild wound healing properties. Additionally, molecular docking simulations confirmed the prodigiosin’s interactions with target proteins, including epidermal growth factor receptor tyrosine kinase (EGFR-TK, PDB ID: 1M17), peptide deformylase from E. faecalis (PDB ID: 2OS1), acidic fibroblast growth factor (FGF-1, PDB ID: 3K1X), PA14_16140 protein from P. aeruginosa (PDB ID: 8Q8O), and human peroxiredoxin 5 (PDB ID: 1HD2) for explaining the anticancer, antibacterial, wound healing, antibiofilm, and antioxidant activities, respectively. Prodigiosin had favorable binding affinities and putative modes of action across various therapeutic domains.ConclusionThis study pioneers the use of prodigiosin as a natural alternative to synthetic medicine since it fights germs, heals wounds, is antioxidant, and reduces biofilm formation.Clinical trial numberNot applicable.

Targeting eIF4G1-dependent translation in melanoma.

Elevated expression of components of eIF4F translation initiation complex has been documented in cancer, resulting in enhanced translation of mRNAs encoding pro-tumorigenic factors, including oncogenic proteins. We previously identified SBI-756, a small molecule that interferes with the eIF4F assembly and overcomes melanoma resistance to BRAF inhibitors. SBI-756 enhanced anti-tumor immunity in pancreatic cancer and was effective in the treatment of diffuse large B cell lymphoma. Here, we identified the eIF4G1 MA3 (4G1-MA3) domain as the target of SBI-756, attenuating eIF4F complex assembly. Melanoma cells expressing a mutant form of 4G1-MA3 exhibited polysome profiles resembling those of melanoma cells treated with SBI-756. A structure-based in silico screen against the eIF4G1 MA3 domain identified M19, a small molecule inhibitor that exhibited anti-melanoma effects. RNA sequencing (RNA-seq) revealed upregulation of UPR, mTOR, p53, and ROS signaling in M19-treated melanoma cells. Ribosome sequencing identified changes in ribosomal structure and electron transport chain components following M19-6 treatment of melanoma cells. Autophagy and histone deacetylase inhibitors were found to enhance anti-neoplastic activities of M19 or its analog, M19-6. M19-6 conferred a greater effect on melanoma than melanocytes and overcame melanoma resistance to BRAF or MEK inhibitors. Alone, M19-6 reduced melanoma growth and metastasis in a xenograft model. M19-6 offers a new therapeutic modality to overcome resistance and metastasis.

Discovery of novel azo pyrimidinone derivatives as B-cell lymphoma-2 inhibitors with potential antineoplastic activity: Synthesis, characterization, in-silico, and in-vitro studies

In the present investigation, novel azo compounds containing pyrimidinone moiety incorporated with different heterocycles were synthesized and characterized using spectroscopic techniques including FT-IR, 1H-NMR, 13C-NMR, and elemental analysis. These azo derivatives were assessed in- silico to determine how well they could inhibit the antiapoptotic B-cell lymphoma-2 (Bcl-2) protein while providing information about their pharmacokinetic characteristics. Our results elucidated that the majority of these new compounds demonstrated moderate to strong binding energies against Bcl-2 target protein comparable to that of venetoclax FDA-approved Bcl-2 inhibitor. Compound 4 showed the top-ranked binding energy followed by compound 5 and compound 3 with values equal to -11.65, -9.53, and -7.82 kcal/mol respectively, while compounds 6 and 7 showed moderate binding energies compared with venetoclax drug that give binding energy equal to -6.95 kcal/mol Furthermore, the in-vitro investigations observed that compounds 4, 5 and 3 demonstrated superior anticancer efficacy against HepG2 and MCF-7 compared to venetoclax drug that gives IC50 equal to 5.10±0.54 and 4.17±0.8 μM respectively. Moreover, all newly synthesized compounds had no cytotoxic impact on WI-38 normal cells contrary to venetoclax drug (26.72±0.94 μM) which was confirmed also through ADMES drug-likeness scores study. Additionally, compounds 4, 5, and 3 revealed an efficient antioxidant scavenging capacity towards DPPH free radicals while compounds 6 and 7 showed a weak scavenging effect compared with standard L. ascorbic acid. Ultimately, the newly synthesized pyrimidinone compounds 4, 5, and 3 that were examined showed encouraging apoptotic and antiproliferative properties. Further, in upcoming clinical studies, the newly synthesized pyrimidinone compounds may prove to be effective anticancer medicines.

Effects of sulforaphane on prostate cancer stem cells-like properties: In vitro and molecular docking studies

The increasing incidence of prostate cancer worldwide has spurred research into novel therapeutics for its treatment and prevention. A critical factor contributing to its incidence and development is the presence of prostate cancer stem cells (PCSCs). Targeting PCSCs has become key in enhancing therapeutic and clinical outcomes of prostate cancer. Sulforaphane (SFN), a compound found in cruciferous vegetables, has shown effective antineoplastic activity in prostate cancer. Yet, its mechanisms of action in PCSCs remains unclear. In the present study, tumorsphere formation assay was used to isolate and enrich PCSCs from PC-3 cells. Our results found that SFN effectively reduced the activity of PCSCs, including the ability of tumorsphere formation, the number of CD133 positive cells, and the expression of PCSCs markers. Moreover, the data showed that SFN inhibited PCSCs through downregulating the activation of Wnt/β-catenin and hedgehog signaling pathways in PCSCs. Furthermore, the verification experiments showed that the activators of Wnt/β-catenin (LiCl) and hedgehog (purmorphamine) attenuated the effects of SFN on PCSCs, including the expression of stem cell markers, cell proliferation and apoptosis. Meanwhile, suppression of β-catenin or Smoothened enhanced the effects of SFN on PCSCs. In addition, molecular docking further indicated that SFN inhibited Wnt/β-catenin and hedgehog pathways by directly targeting β-catenin and Smoothened. Taken together, our results demonstrated that SFN targeted PCSCs through Wnt/β-catenin and hedgehog pathways to inhibit stemness and proliferation and induce apoptosis. Findings from this study could provide new insights into SFN as a dietary supplement or adjunct to chemotherapy.

SURG-27. DIRECTIONALLY NON-ROTATING ELECTRIC FIELD THERAPY (DNEFT) DELIVERED THROUGH IMPLANTED ELECTRODES: A NOVEL SURGICAL PLATFORM FOR GLIOBLASTOMA IMMUNOTHERAPY

Abstract BACKGROUND While directionally rotating Tumor Treating Fields (TTF) therapy has garnered considerable clinical interest in recent years, there has been comparatively less focus on directionally non-rotating electric field therapy (dnEFT). OBJECTIVE Here, we explore dnEFT generated through implanted electrodes as a glioblastoma therapeutic platform, with the goal of facilitating clinical translation. METHODS Using custom-designed electrode arrays to study the effect of dnEFT using in vitro and in vivo glioblastoma models. RESULTS In vitro, dnEFT generated using a clinical grade spinal cord stimulator showed anti-neoplastic activity against independent glioblastoma cell lines. In support of the results obtained using the clinical grade electrode, dnEFT delivered through a customized, two-electrode array induced glioblastoma apoptosis. To characterize this effect in vivo, a custom-designed four-electrode array was fabricated such that tumor cells can be implanted into murine cerebrum through a center channel equidistant from the electrodes. After implantation with this array and luciferase expressing murine GL261 glioblastoma cells, mice were randomized to dnEFT or placebo. Relative to placebo treated mice, dnEFT reduced tumor growth (measured by bioluminescence) and prolonged survival (median survival gain of 6.5 days). Analysis of brain sections following dnEFT showed a notable increase in the accumulation of peri-tumoral macrophage/microglia with increased expression of M1 genes (IFNγ, TNFα, IL-6) and decreased expression of M2 genes (CD206, Arg, IL-10) relative to placebo tumors. CONCLUSIONS Our results suggest therapeutic potential in glioblastoma for dnEFT delivered through implanted electrodes as a novel immunotherapy platform, supporting the concept of a proof-of-principle clinical trial using commercially available deep brain stimulator electrodes.

Anti-inflammatory effects of eupatilin on Helicobacter pylori CagA-induced gastric inflammation.

Eupatilin, a flavone isolated from Artemisia species, exerts anti-inflammatory, anti-oxidative, and anti-neoplastic activities. However, the effects of eupatilin on H. pylori-associated gastritis remain unclear. Thus, this study aimed to investigate the anti-inflammatory effects of eupatilin on gastric epithelial cells infected with cytotoxin-associated gene A (CagA)-positive Helicobacter pylori. AGS human gastric carcinoma cells were infected with a CagA-positive H. pylori strain and then treated with 10, 50, or 100 ng of eupatilin. After 24 h, the expression levels of CagA, phosphoinositide 3-kinase 1 (PI3K), nuclear factor (NF)-κB, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α in the cell lysates were measured using western blotting, and the mRNA levels of IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 were measured using real-time polymerase chain reaction. CagA translocation into AGS cells resulted in an elongated cell morphology, which was significantly suppressed by eupatilin treatment in a dose-dependent manner. Immunofluorescence staining for anti-CagA showed that eupatilin treatment dose-dependently inhibited CagA expression in the H. pylori-infected AGS cells. H. pylori infection increased the levels of pro-inflammatory cytokines including IL-1β, TNF-α, IL-6, IL-8, and MCP-1, and eupatilin treatment significantly reduced the levels of these cytokines in a dose-dependent manner. Additionally, eupatilin treatment dose-dependently suppressed the expression of PI3K and NF-κB. Eupatilin treatment demonstrated anti-inflammatory effects on CagA-positive H. pylori-infected gastric epithelial cells by inhibiting CagA translocation, thereby suppressing the NF-κB signaling pathway. These results suggest that eupatilin plays a protective role against CagA-positive H. pylori-induced gastritis.