Malignant Cell Lines Research Articles

Novel 5-Fluorouracil analogues versus perfluorophenyl ureas as potent anti-breast cancer agents: Design, robust synthesis, in vitro, molecular docking, pharmacokinetics ADMET analysis and dynamic simulations

To investigate the therapeutic potential of 5-Fluorouracil-based analogues, a straightforward synthetic technique was employed to synthesize a novel series of 5-arylurea uracil derivatives (AUFU01-03) and aryl-urea derivatives bearing perfluorophenyl (AUPF01-03). Reliable tools such as infrared (IR), Nuclear Magnetic Resonance (NMR) spectra, and elemental analyses were utilized to confirm the chemical structures and purity of these compounds. In comparison to healthy noncancerous control skin fibroblast cells (BJ-1), we examined the antiproliferative efficacy of compounds (AUFU01-03) and (AUPF01-03) against specific human malignant cell lines of the breast (MCF-7), and colon (HCT-116). Based on the MTT experiment results, compounds AUFU03 and AUPF01-03 possessed highly cytotoxic effects. Among these, cytotoxicity was demonstrated by compounds AUPF01-03 with IC50 values (AUPF01, IC50 = 167 ± 0.57 µM, AUPF02, IC50 = 23.4 ± 0.68 µM and AUPF03, IC50 = 28.8 ± 1.13 µM, respectively, on MCF-7), relative to 5-Fluorouracil as reference drug (IC50 = 160.7 ± 0.22 µM). Compound AUPF01 showed safety on BJ-1 cells up to a concentration of 100 µM (% cytotoxicity = 3.9 ± 0.42 %), so AUPF01 was selected for further studies. At the gene, the expression levels of BCL-2 gene were decreased significantly in MCF-7 + 5-FU and reached the lowest level in MCF-7 + AUPF01. In contrast, the expression levels of pro-apoptotic genes (p53 and BAX) were increased in MCF-7 + 5-FU, and reached a significantly higher level in MCF-7 + AUPF01. Apoptosis/necrosis assays demonstrated that AUPF01 induced S and G2/M phase cell cycle arrest in MCF-7 cells. Moreover, the efficacy of these compounds against anti-cancer protein receptors was assessed using molecular docking. The results indicated that compound AUPF01 exhibited high binding energies, effectively interacting with the active sites of crucial proteins such as EGFR, CDK2, ERalfa, BAX1, BCL2, and P53. These interactions involved a diverse range of chemical bonding types, suggesting the potential of these substances to inhibit enzyme activities. Moreover, computational ADMET analyses of these compounds demonstrated compliance with Lipinski’s criteria, indicating favorable physicochemical properties. Additionally, molecular dynamics (MD) simulations revealed stable complexes of AUPF01 with EGFR, CDK2, ERalfa, BAX1, BCL2, and P53, as evidenced by (RMSD) values, RMSF values, and (SASA) values for the respective complexes.

QbD-driven Formulation Development and Evaluation of Genistein Nanoparticles for Prostate Cancer

Background: Genistein (GEN) shows significant anticancer potential, particularly against prostate cancer. However, its clinical application is limited by poor water solubility, rapid metabolism and excretion, low bioavailability, and lack of targeted delivery to cancer cells, hindering its effectiveness as a chemopreventive or therapeutic agent. Objective: In this study, poly-ε-caprolactone (PCL) nanoparticles incorporating polyvinyl alcohol (PVA) as a stabilizer were engineered to encapsulate genistein (GEN) effectively. Utilizing a Quality by Design (QbD) methodology, the development and optimization of these nanoparticles were systematically approached. Methods: GEN-loaded PCL nanoparticles (NPs) were prepared using the Solvent Evaporation Technique, ideal for encapsulating hydrophobic drugs. A Plackett–Burman design (PBD) identified key factors, followed by a Box–Behnken design (BBD) to optimize nanoparticle quality. The NPs were evaluated for particle size, zeta potential (ZP), polydispersity index (PDI), morphology, encapsulation efficiency (EE), in vitro drug release, and cytotoxicity. Results: The optimized formulation containing PCL, PVA, and Volume of organic solvent as 43.7 mg, 6.2 mg, and 10.0 ml, respectively was chosen because it showed EE (%) of 94.0%, average particle size of 150 nm, PDI of 0.10, ZP of -28.0 and exhibited sustained release of GEN for around four days. The antiproliferative activities of GEN PCL NPs were confirmed by the MTT test in vitro on malignant prostate carcinoma cell lines (PC3). Flow cytometric analysis showed that the inhibition of cell proliferation of more potent GEN PCL NPs is comparable with the effects of free GEN. Conclusion: The findings indicate that genistein-loaded PCL nanoparticles have the potential to augment the anticancer efficacy of genistein, both in vitro and in vivo. This suggests their promise as a viable candidate for prostate cancer treatment.

Targeting CD5 chimeric antigen receptor-engineered natural killer cells against T-cell malignancies

BackgroundChimeric antigen receptor engineered T cells (CAR-T) have demonstrated promising clinical efficacy in B-cell malignancies, and the approach has been extended to T-cell malignancies. However, the use of allogeneic T cells in CAR therapy poses a challenge due to the risk of graft-versus-host disease. Recently, natural killer (NK) cells have exhibited “off‑the‑shelf” availability. The nanobody-based CAR structures have attracted much attention for their therapeutic potential owing to the advantages of nanobody, including small size, optimal stability, high affinity and manufacturing feasibility. CD5, a common surface marker of malignant T cells, has three scavenger receptor cysteine-rich domains (D1-D3) in the extracellular region. The present study aims to construct “off‑the‑shelf” CAR-NK cells targeting the membrane-proximal domain of CD5 derived from nanobody against T-cell malignancies.MethodsAnti-CD5-D3 nanobody was screened by phage display technology, followed by constructing fourth-generation CAR plasmids ectopically producing IL-15 to generate CD5 CAR-NK cells derived from peripheral blood. And the second-generation CD5 CAR-T cells based on nanobody were generated, referred to as 5D.b CAR-T and 12 C.b CAR-T. Furthermore, CAR-NK cells without IL-15 (IL-15△ CAR-NK) were generated to assess the impact on cytotoxicity of CAR-NK cells. Cytotoxic activity against CD5+ hematologic malignant cell lines and normal T cells was exerted in vitro and NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt mouse model transplanted with Jurkat-Luc cells was used to evaluate the antitumor efficacy of CD5 CAR-NK cells in vivo.ResultsTwo nanobodies (5D and 12 C) competed for binding to the epitope of CD5-D3. 12 C CAR-NK cells were superior to 5D CAR-NK cells in antitumor potential and 12 C.b CAR-T cells exhibited superior cytotoxic activity than 5D CAR-T cells ex vivo. So, 12 C was regarded as the optimal nanobody. 12 C CAR-NK cells and IL-15△ CAR-NK cells exhibited robust cytotoxicity against CD5+ malignant cell lines and controlled disease progression in xenograft mouse model. 12 C CAR-NK cells demonstrated greater antitumor activity compared to that of IL-15△ CAR-NK cells in vitro and in vivo.ConclusionsTaken together, the fourth-generation nanobody-derived anti-CD5 CAR-NK cells may be a promising therapeutic against T-cell malignancies.

Genes Related to Motility in an Ionizing Radiation and Estrogen Breast Cancer Model

Breast cancer is a major global health concern as it is the primary cause of cancer death for women. Environmental radiation exposure and endogenous factors such as hormones increase breast cancer risk, and its development and spread depend on cell motility and migration. The expression of genes associated with cell motility, such as ADAM12, CYR61, FLRT2, SLIT2, VNN1, MYLK, MAP1B, and TUBA1A, was analyzed in an experimental breast cancer model induced by radiation and estrogen. The results showed that TUBA1A, SLIT2, MAP1B, MYLK, and ADAM12 gene expression increased in the irradiated Alpha3 cell line but not in the control or the malignant Tumor2 cell line. Bioinformatic analysis indicated that FLERT2, SLIT2, VNN1, MAP1B, MYLK, and TUBA1A gene expressions were found to be higher in normal tissue than in tumor tissue of breast cancer patients. However, ADAM12 and CYR61 expressions were found to be higher in tumors than in normal tissues, and they had a negative correlation with ESR1 gene expression. Concerning ESR2 gene expression, there was a negative correlation with CYR61, but there was a positive correlation with FLRT2, MYLK, MAP1B, and VNN1. Finally, a decreased survival rate was observed in patients exhibiting high expression levels of TUBA1A and MAP1B. These genes also showed a negative ER status, an important parameter for endocrine therapy. The genes related to motility were affected by ionizing radiation, confirming its role in the initiation process of breast carcinogenesis. In conclusion, the relationship between the patient’s expression of hormone receptors and genes associated with cell motility presents a novel prospect for exploring therapeutic strategies.

Transcriptome analysis reveals a role of FOXO3 in antileukemia/lymphoma properties of panduratin A

Boesenbergia rotunda, commonly known as fingerroot, is a medicinal and culinary plant native to the Indochina Peninsula. We found that panduratin A (Pan-A), one of the compounds present in the rhizome extract of fingerroot, inhibited cell proliferation, induced apoptosis, and promoted cell cycle arrest at G0/G1 phase in multiple hematologic malignant cell lines including leukemia and lymphoma lines. Pan-A inhibited these activities in leukemia and lymphoma cells in a concentration-dependent manner. High-throughput transcriptome analysis indicated that Pan-A is involved in the cell cycle, cellular senescence, apoptosis, and multiple canonical signaling pathways in lymphoma cells. The Forkhead box O (FOXO) transcription factor family was identified as a potential target of Pan-A. Western blot showed elevated caspase 7 and cPARP/PARP in the B-cell lymphoma cells after treatment with Pan-A. The inhibitory effects were accompanied by stimulation of Akt signaling and phosphorylation of FOXO3. Immunohistochemistry of tissues from patients with B-cell lymphoma revealed detectable levels of FOXO3 protein specifically in neoplastic B cells. Overall, our results highlight FOXO3 as a player underlying antileukemia/lymphoma effects of Pan-A.

Unraveling the therapeutic potential of Satureja nabateorum extract: inducing apoptosis and cell cycle arrest through p53, Bax/Bcl-2, and caspase-3 pathways in human malignant cell lines, with in silico insights

Satureja nabateorum, known as Nabatean savory is a Lamiaceae plant native to the Arabian Peninsula, specifically in the mountainous regions of Saudi Arabia. The study aims to investigate the phytochemical components of the S. nabateorum leaves (SNL) and stems (SNS) extract and to assess their antioxidant, antimicrobial, and antiproliferative properties. Methanol extracts from leaves and stems were analyzed for chemical constituents using the GC-MS technique. Antioxidant capacities were measured using hydrogen peroxide and ABTS radical-scavenging methods, and antimicrobial activity was tested against various microorganisms. Cytotoxic activity on four human malignant cell lines was assessed using MTT and flow cytometry. Molecular docking and molecular dynamics studies were conducted to understand the interactions and binding modes of the extracted compounds at a molecular level. GC-MS analysis of SNL extract revealed thymol, carvacrol, and p-cymen-8-ol as major constituents. SNS extract contained β-sitosterol, stigmasterol, lupeol, and lup-20(29)-ene-3β,28-diol. SNS extract exhibited more potent antioxidant, antimicrobial, and anticancer effects than SNL extract. The extract, SNS, exhibited potential toxicity in A549 cells with an IC50 value of 3.62 µg/mL and induced marked apoptotic effects with S phase-cell cycle arrest. SNS extract also showed higher levels of Caspase 3, Bax, p53, and the Bax/Bcl2 ratio and lower levels of Bcl-2. Molecular docking and dynamic simulation supported these findings, targeting the EGFR TK domain. The study suggests that the S. nabateorum stem extract holds promise as a potent antimicrobial, antioxidant, and anticancer agent. It provides valuable insights for considering the extract as a substitute for chemotherapy and/or protective agents.

Different Doxorubicin Sensitivity Across Various Human Cancer Cell Lines

Doxorubicin (Dox) is a highly potent chemotherapeutic agent, approved by FDA since 1974, for treating a broad spectrum of cancers. However, development of severe side effects and drug resistance are main issues that limit the clinical use of Dox. Herein, we aimed to investigate the sensitivity of Dox in a variety of human cancer cell lines. Eleven cell lines were tested in this study including 2 hepatocellular carcinoma (HCC) cell lines (HepG2 and Huh7), 4 bladder cancer (BlCa) cell lines (UMUC-3, VMCUB-1, TCCSUP and BFTC-905), a lung cancer cell line (A549), a cervical carcinoma cell line (HeLa), a breast cancer cell line (MCF-7), a skin melanoma cell line (M21) and a noncancer human kidney cell line (HK-2). The MTT assay was employed for the determination of cytotoxicity. Cells were treated with various concentrations of Dox for 24 h. The half-maximal inhibitory concentration (IC50) of Dox was calculated to compare the Dox sensitivity among tested cell lines. The result showed that IC50 of Dox in HepG2, Huh7, UMUC-3, VMCUB-1, TCCSUP, BFTC-905, A549, HeLa, MCF-7, M21 and HK-2 cells were 12.2, > 20, 5.1, > 20, 12.6, 2.3, > 20, 2.9, 2.5, 2.8 and > 20 mM, respectively. BFTC-905 had the lowest IC50 value, therefore, it was the most sensitive to Dox. In contrast, Huh7, VMCUB-1 and A549 cells were resistant to Dox with IC50 values > 20 mM. Conclusions, we demonstrated that different human malignant cell lines had different sensitivity to Dox. BFTC-905 BlCa cell line had the highest sensitivity to Dox. Huh7, VMCUB-1 and A549 cell lines were resistant to Dox. Perhaps, the different Dox sensitivity in different cell lines was due to the different acquisition of Dox resistance mechanisms. Huh7, VMCUB-1 and A549 cell lines could be suitable cell models to investigate the molecular mechanism of Dox resistance in different cancers. HIGHLIGHTS Different types of cancer cell lines exhibited different sensitivity to doxorubicin. BFTC-905, MCF-7 and M21 cell lines were sensitive to doxorubicin. HepG2, UMUC-3, TCCSUP and HeLa cells were moderately sensitive to doxorubicin. Huh7, VMCUB-1, A549 and HK-2 cells were resistant to doxorubicin. Huh7, VMCUB-1 and A549 cell lines could be suitable cell models for investigating the molecular pathways of Dox resistance in different types of cancers. GRAPHICAL ABSTRACT

Anticancer Activity of Vitamin D, Lumisterol and Selected Derivatives against Human Malignant Melanoma Cell Lines.

Despite the recent development of improved methods of treating melanoma such as targeted therapy, immunotherapy or combined treatment, the number of new cases worldwide is increasing. It is well known that active metabolites of vitamin D3 and lumisterol (L3) exert photoprotective and antiproliferative effects on the skin, while UV radiation is a major environmental risk factor for melanoma. Thus, many natural metabolites and synthetic analogs of steroidal and secosteroidal molecules have been tested on various cancer cells and in animal models. In this study, we tested the anti-melanoma properties of several natural derivatives of vitamin D3 and L3 in comparison to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). A significant decrease in melanoma cell proliferation and cell mobility was observed for selected derivatives, with (25R)-27-hydroxyL3 showing the highest potency (lowest IC50) in A375 cells but lower potency in SK-MEL-28 cells, whereas the parent L3 failed to inhibit proliferation. The efficacy (% inhibition) by 1,24,25(OH)3D3 and 1,25(OH)2D3 were similar in both cell types. 1,25(OH)2D3 showed higher potency than 1,24,25(OH)3D3 in SK-MEL-28 cells, but lower potency in A375 cells for the inhibition of proliferation. As for 1,25(OH)2D3, but not the other derivatives tested, treatment of melanoma cells with 1,24,25(OH)3D3 markedly increased the expression of CYP24A1, enhanced translocation of the vitamin D receptor (VDR) from the cytoplasm to the nucleus and also decreased the expression of the proliferation marker Ki67. The effects of the other compounds tested were weaker and occurred only under certain conditions. Our data indicate that 1,24,25(OH)3D3, which has undergone the first step in 1,25(OH)2D3 inactivation by being hydroxylated at C24, still shows anti-melanoma properties, displaying higher potency than 1,25(OH)2D3 in SK-MEL-28 cells. Furthermore, hydroxylation increases the potency of some of the lumisterol hydroxy-derivatives, as in contrast to L3, (25R)-27(OH)L3 effectively inhibits proliferation and migration of the human malignant melanoma cell line A375.

The Antarctic Yeast Sporobolomyces roseus AL103 as a Promising Source of Health-Promoting Biologically Active Compounds

Antarctic yeasts represent a poorly explored source of novel bioactive compounds with antineoplastic activity and a favorable toxicological profile. The present paper presents the newest data on the antiproliferative and antimicrobial potential of extracts obtained from the psychrophilic strain AL103 of the species Sporobolomyces roseus. The capacity of AL103 to grow under different cultivation conditions, including in a bioreactor system with optimal biomass quantities of approximately 6.0 g/L, was demonstrated. A comparative examination of the metabolic profiles (GC-MS-based) of yeast extracts revealed a wide variety of synthesized molecules responsible for the different levels of antineoplastic activity depending on the tissue origin of the malignant cell lines. Concentration response curves were generated by the MTT dye reduction test. The respective IC50 values were extrapolated and found between 35.3 and 163 µg/mL. The antibacterial potential of both extracts was evaluated with the broth microdilution test against four referent pathogenic bacterial strains. The estimated minimal inhibitory concentrations revealed a moderate antibacterial activity. According to the GC-MS results, both extracts are rich in long-chain fatty acids which are known for their antibacterial properties. In conclusion, the Antarctic strain AL103 possesses promising potential for further pharmacological investigations aiming to elucidate its application as a health-promoting food additive or/and as a source of biologically active compounds.

Convenient Synthesis, Characterizations and Biological Evolution of Novel 1‐Phenyl‐N’‐(3‐phenylacryloyl)cyclopropane carbohydrazide Derivatives

AbstractCancer is a longstanding worldwide issue, current chemotherapeutic treatments have limited effectiveness and high toxicity. An extensive investigation has revealed a significant potential link between ITK and the development of cancer. Hence, it is recommended to prioritize investigating ITK to develop and produce novel inhibitors for treating diseases associated with T cells. In our study, we have designed and synthesized two new series of compounds, which consist of cinnamic acid, carbohydrazide, and cyclopropanamide groups in a single compound. We have developed a facile method to synthesize 20 new derivatives of two series of innovative 1‐phenyl‐N’‐(3‐phenylacryloyl)cyclopropane carbohydrazide derivatives with good yields and purity. The Synthesized derivatives are conformed by analytical techniques (FT‐IR, 1H NMR, 13C NMR, elemental analysis) and their biological evaluation data is provided. The synthesized compounds displayed favorable docking scores in comparison to the ITK inhibitor, Ibrutinib. The in vitro cancer investigation shows that these compounds have good IC50 values, causing cytotoxicity against malignant cell lines.

Chlorine containing tetrahydropyrimidines: Synthesis, characterization, anticancer activity and mechanism of action

The aim of the presented research was to explore anticancer potential of eleven newly synthesized tetrahydropyrimidine derivatives. The compounds were synthesized via Biginelli multicomponent one-pot reaction using different derivatives of vanillin, ethyl 4-chloroacetoacetate and (N-methyl)urea. The cytotoxic effects of the compounds were examined on three human malignant cell lines (HeLa, K562, and MCF7), and normal lung fibroblasts MRC-5. The mechanisms of anticancer activity were examined for two compounds 4a and 4b which showed the strongest and selective cytotoxicity against chronic myelogenous leukaemia K562 cells (IC50 = 1.76 ± 0.09, and.1.66 ± 0.05, respectively). The changes of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor A (VEGFA) were investigated in the K562 cell line, as well as oncomiRNA miR-10b, miR-23a described to have both features, depending on a specific type of malignancy, and miR-34a with mostly described as a tumour suppressor.

Ethyl Oleate, Hexadecenoic Acid, Phytol Profiling of Onosma bracteatum: Antibacterial, Anticancer and Molecular Docking Studies

Research studies on phytochemicals and antibiotics utilizing extracts from medicinal plants have proliferated in the past few years. The phytochemicals profiling, antioxidant capacity, antibacterial properties, antiproliferative potential and molecular docking studies of ethanolic extract of Onosma bracteatum was examined in this study. The extract prepared into ethanol (80%) and identify the presence of phytochemical compounds using GC-MS profiling. The antibacterial potential was investigated in relation to Staphylococcus aureus and Escherichia coli. Further to evaluate the anticancer potential of ethanolic extract of O. bracteatum, the antiproliferative assay (MTT cytotoxicity assay) was performed against Ln-18 (human malignant glioma cell line) and A-549 (Human lung cancer cell line) cells. Ethyl oleate, hexadecenoic acid and phytol were highest in GC-MS and docked against DNA gyrase B (E. coli), β-lactamase (S. aureus) and BCL-2 (apoptosis inhibitor). In antioxidant assay, 78% maximum inhibition of free radical scavenging activity was observed. The zone of inhibition was in the ranges from 9 mm (E. coli) to 20 mm (S. aureus). Furthermore, the ethanolic extract of O. bracteatum demonstrated antiproliferative activity against the cancer cell lines LN-18 and A-549 with growth inhibitions of 84% and 81%. The ethyl oleate was found to be best compound with -8.4 (kcal/mol) binding score in the molecular docking studies. The results showed that O. bracteatum is a good source of phytochemicals and antibacterial compounds with promising anticancerous potential.

Impact of Proton Irradiation Depending on Breast Cancer Subtype in Patient-Derived Cell Lines

Research on different types of ionizing radiation’s effects has been ongoing for years, revealing its efficacy in damaging cancer cells. Solid tumors comprise diverse cell types, each being able to respond differently to radiation. This study evaluated the radiobiological response of established (MDA-MB-231 (Triple negative breast cancer, TNBC), MCF-7 (Luminal A)) and patient-derived malignant cell lines, cancer-associated fibroblasts, and skin fibroblasts following proton IRR. All cell line types were irradiated with the proton dose of 2, 4, and 6 Gy. The radiobiological response was assessed using clonogenic assay, γH2AX, and p53 staining. It was noticeable that breast cancer lines of different molecular subtypes displayed no significant variations in their response to proton IRR. In terms of cancer-associated fibroblasts extracted from the tumor tissue, the line derived from a TNBC subtype tumor demonstrated higher resistance to ionizing radiation compared to lines isolated from luminal A tumors. Fibroblasts extracted from patients’ skin responded identically to all doses of proton radiation. This study emphasizes that tumor response is not exclusively determined by the elimination of breast cancer cells, but also takes into account tumor microenvironmental variables and skin reactions.

Effect of Different Glucose Levels and Glycation on Meningioma Cell Migration and Invasion.

Meningiomas are predominantly benign tumors, but there are also malignant forms that are associated with a poor prognosis. Like almost all tumors, meningiomas metabolize glucose as part of aerobic glycolysis (Warburg effect) for energy supply, so there are attempts to influence the prognosis of tumor diseases using a glucose-reduced diet. This altered metabolism leads to so called hallmarks of cancer, such as glycation and glycosylation. In this study, we investigated the influence of low (3 mM), normal (5.5 mM) and high glucose (15 mM) on a malignant meningioma cell line (IOMM-Lee, WHO grade 3). In addition, the influence of methylglyoxal, a by-product of glycolysis and a precursor for glycation, was investigated. Impedance-based methods (ECIS and RTCA) were used to study migration and invasion, and immunoblotting was used to analyze the expression of proteins relevant to these processes, such as focal adhesion kinase (FAK), merlin or integrin ß1. We were able to show that low glucose reduced the invasive potential of the cells, which was associated with a reduced amount of sialic acid. Under high glucose, barrier function was impaired and adhesion decreased, which correlated with a decreased expression of FAK.

Combination of JAKi and HDACi Exerts Antiangiogenic Potential in Cutaneous T-Cell Lymphoma.

Angiogenesis plays a pivotal role in the growth and metastasis of tumors, including the development and progression of cutaneous lymphomas. The chick embryo CAM model has been utilized in various studies to assess the growth rate, angiogenic potential, and metastatic capability of different tumor types and malignant cell lines. However, the precise mechanisms of angiogenesis in CTCL and the influence of Ruxolitinib or Resminostat on angiogenesis in hematological malignancies and solid tumors are not well understood. Recent in vitro and in vivo data have demonstrated the synergistic inhibition of tumorigenesis and metastasis in experimental models of CTCL when using the combination of Resminostat (HDACi) with Ruxolitinib (JAKi). The present work aims to elucidate the effects of this combination on the tumor microenvironment's vascular components. We investigated the effects of Ruxolitinib (JAKi) in combination with Resminostat (HDACi) treatment in transendothelial migration of CTCL cells (106 MyLa and SeAx) by using a transwell-based transendothelial migration assay and tumor angiogenesis in vivo. We used the CTCL chick embryo CAM model with xenografted tumors derived from implanted MyLa and SeAx cells and administered topically 15 μM ruxolitinib and 5 μM Resminostat every two days during a 5-day period. JAKi and HDACi inhibited CTCL cell transendothelial migration by 75% and 82% (p < 0.05) in both CTCL engrafted cells (MyLa and SeAx, respectively) compared to the untreated group. Moreover, the combination of ruxolitinib with resminostat blocked angiogenesis by significantly reducing the number of blood vessel formation by 49% and 34% in both MyLa and SeAx, respectively (p < 0.05), indicating that the proposed combination exerted significant anti-angiogenic effects in the CAM CTCL model. Overall, these data provide valuable insights into potential therapeutic strategies targeting angiogenesis in CTCL, paving the way for more effective treatment approaches in the future.

The Z isomer of pyridoxilidenerhodanine 5'-phosphate is an efficient inhibitor of human pyridoxine 5'-phosphate oxidase, a crucial enzyme in vitamin B6 salvage pathway and a potential chemotherapeutic target.

Pyridoxal 5'-phosphate (PLP), the catalytically active form of vitamin B6, acts as a cofactor in many metabolic processes. In humans, PLP is produced in the reactions catalysed by pyridox(am)ine 5'-phosphate oxidase (PNPO) and pyridoxal kinase (PDXK). Both PNPO and PDXK are involved in cancer progression of many tumours. The silencing of PNPO and PDXK encoding genes determines a strong reduction in tumour size and neoplastic cell invasiveness in models of acute myeloid leukaemia (in the case of PDXK) and ovarian and breast cancer (in the case of PNPO). In the present work, we demonstrate that pyridoxilidenerhodanine 5'-phosphate (PLP-R), a PLP analogue that has been tested by other authors on malignant cell lines reporting a reduction in proliferation, inhibits PNPO in vitro following a mixed competitive and allosteric mechanism. We also show that the unphosphorylated precursor of this inhibitor (PL-R), which has more favourable pharmacokinetic properties according to our predictions, is phosphorylated by PDXK and therefore transformed into PLP-R. On this ground, we propose the prototype of a novel prodrug-drug system as a useful starting point for the development of new, potential, antineoplastic agents.

Synthesis, Characterization, and Biological Evaluation of Novel [M(η6-arene)2]+ (M = Re, 99mTc) Hosted Terpyridines and Copper Complexes Thereof.

We report the synthesis, characterization, and in vitro biological activities of [Re(η6-arene)2]+-terpyridine conjugates and their CuII complexes. The terpyridine (terpy) chelators were attached to the [Re(η6-arene)2]+ scaffold via secondary amine linkers allowing for heteroleptic mono- and homoleptic bis-terpyridine-substituted chelators. Complexation with CuCl2 afforded the respective square pyramidal [Cu(terpy)Cl2] complexes hosted on the [Re(η6-arene)2]+ scaffold. The chelator conjugates and their respective complexes were found to be remarkably cytotoxic against malignant HT29 and A549 human cancer cell lines in vitro with IC50 values in the low micromolar range. Mitochondrial respiration disruption was identified as a possible mode of action of these novel drug candidates. Crucially, the [Re(η6-arene)2]+ hosts delivered water solubility of the otherwise insoluble [Cu(terpy)Cl2] motif. Importantly, the homoleptic [99mTc(η6-arene)2]+-terpyridine conjugate is available in a single step, which enables the presented system to be used as a theranostic approach to modern medicinal inorganic chemistry.

Phytochemical analysis, antioxidant, anticancer, and antibacterial potential of Alpinia galanga (L.) rhizome

Alpinia galanga (L.) Willd. (A. galanga) is extremely significant and is utilized extensively in traditional medicine throughout many nations. This study aimed to determine the chemical composition of A. galanga rhizome extract (AgRE) and to evaluate its antioxidant, anticancer, and antibacterial activities. The total phenolic content (TPC) and total flavonoid content (TFC) of AgRE were determined. The antioxidant activity, cytotoxic capability, and antibacterial of were assessed, as well as anti-apoptotic genes. Molecular docking (MD) was used to assess the binding affinity of the most enriched constituents in AgRE toward the active sites of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and p53 tumor suppressor protein (TP53). Gas chromatography-mass spectrometry (GC-MS) analysis demonstrated that AgRE is a rich source of turmerone. AgRE had moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging properties, with the half-maximal inhibitory concentration (IC50) values of 79.34 ± 1.78 and 88.94 ± 2.28 μg/ml, respectively. AgRE preferentially reduced the viability of a subset of malignant MCF-7 and HepG2 cell lines, with IC50 of 125.35 ± 4.28 and 182.49 ± 3.19 μg/ml, respectively. AgRE exhibited considerable antimicrobial activity against all bacterial strains, with MIC values ranging from 7.81 ± 1.53 to 62.5 ± 3.28 μg/ml. The MD results revealed that ethyl-4-(2-methylpropyl)-benzene had the greatest binding energy with NADPH oxidase, with a Glide score of −6848 kcal/mol, followed by 2-methoxy-phenol (−5111 kcal/mol). Taken together, we report the interesting antioxidant, antibacterial, and anticancer properties of AgRE, which warrant further investigation. AgRE is a promising natural resource that could be used to combat complicated diseases such as cancer and bacterial infections.

CEP-1347 Boosts Chk2-Mediated p53 Activation by Ionizing Radiation to Inhibit the Growth of Malignant Brain Tumor Cells.

Radiation therapy continues to be the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Therefore, the identification of drugs that promote the ionizing radiation (IR)-induced activation of p53 is expected to increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, while their combination did not result in further decreases. CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. The present results show, for the first time, that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR in addition to inhibiting the expression of MDM4 and, thus, CEP-1347 has potential as a radiosensitizer for malignant brain tumors expressing wild-type p53.

Terrein Exhibits Anti-tumor Activity by Suppressing Angiogenin Expression in Malignant Melanoma Cells.

Malignant melanoma is a tumor with a poor prognosis that can metastasize distally at an early stage. Terrein, a metabolite produced by Aspergillus terreus, suppresses the expression of angiogenin, an angiogenic factor. However, the pharmacological effects of natural terrein have not been elucidated, because only a small amount of terrein can be extracted from large fungal cultures. In this study, we investigated the antineoplastic effects of terrein on human malignant melanoma cells and its underlying mechanisms. Human malignant melanoma cell lines were cultured in the presence of terrein and analyzed. Angiogenin production was evaluated using ELISA. Ribosome biosynthesis was evaluated using silver staining of the nucleolar organizer region. Intracellular signaling pathways were analyzed using western blotting. Malignant melanoma cells were transplanted subcutaneously into the backs of nude mice. The tumors were removed at 5 weeks and analyzed histopathologically. Terrein inhibited angiogenin expression, proliferation, migration, invasion, and ribosome biosynthesis in malignant melanoma cells. Terrein was shown to inhibit tumor growth and angiogenesis in animal models. This study demonstrated that terrein has anti-tumor effects against malignant melanoma. Furthermore, chemically synthesized non-natural terrein can be mass-produced and serve as a novel potential anti-tumor drug candidate.