Bioinspired thiazolo-[2,3-b] quinazolin-6-one derivatives as potent anti-cancer agents targeting EGFR: their biological evaluations and in silico assessment.

Cancer is a challenging and second most deadly disease. The epidermal growth factor receptors (EGFRs) dimerize upon ligand bindings to the extracellular domain that intiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphrylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. In this study, we unravel the binding mechanism of newly synthesized thiazolo-[2,3-b] quinazolin-6-one and evaluate their anti-cancer activity against ovary and prostate carcinoma cell lines (OVCAR-3 and PC-3). Synthesized molecules exhibited promising anti-cancer activity against OVCAR-3 and PC-3 carcinoma cell lines with inhibitory concentrations ranging from 13.4 ± 0.43 to 23.6 ± 1.22 µM and 7.5 ± 0.62 to 67.5 ± 1.24 µM, respectively. These compounds induced apoptosis and resulted in cell cycle arrest at G1 and G2/M transition phases. Next, the nude mice models were taken to investigate the toxicity of the 4bi compound, and in vivo investigations revealed no effects upon examined organs (liver and kidney) treated at different concentrations. Moreover, the combined in silico approaches, molecular docking, molecular dynamics simulations, and MM/PBSA methods were performed to assess the binding affinity and stability of bioinspired synthesized congeners with the epidermal growth factor receptor tyrosine kinase (EGFR-TK). The free binding energy (ΔGbind) of the 4bi molecule was found comparable to Erlotinib drug. The test molecule could be competent for further usage to determine its efficicacy in cancer therapeutics.

In Vitro Anticancer Properties of Novel Bis-Triazoles.

Here, we describe the anticancer activity of our novel bis-triazoles MS47 and MS49, developed previously as G-quadruplex stabilizers, focusing specifically upon the human melanoma MDA-MB-435 cell line. At the National Cancer Institute (NCI), USA, bis-triazole MS47 (NCS 778438) was evaluated against a panel of sixty human cancer cell lines, and showed selective, distinct multi-log differential patterns of activity, with GI50 and LC50 values in the sub-micromolar range against human cancer cells. MS47 showed highly selective cytotoxicity towards human melanoma, ovarian, CNS and colon cancer cell lines; in contrast, the leukemia cell lines interestingly showed resistance to MS47 cytotoxic activity. Further studies revealed the potent cell growth inhibiting properties of MS47 and MS49 against the human melanoma MDA-MB-435 cell line, as verified by MTT assays; both ligands were more potent against cancer cells than MRC-5 fetal lung fibroblasts (SI > 9). Melanoma colony formation was significantly suppressed by MS47 and MS49, and time- and dose-dependent apoptosis induction was also observed. Furthermore, MS47 significantly arrested melanoma cells at the G0/G1 cell cycle phase. While the expression levels of Hsp90 protein in melanoma cells were significantly decreased by MS49, corroborating its binding to the G4-DNA promoter of the Hsp90 gene. Both ligands failed to induce senescence in the human melanoma cells after 72 h of treatment, corroborating their weak stabilization of the telomeric G4-DNA.

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells.

Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM-T-MEL), indoline (EM-I-MEL), or 4-(4-morpholinyl) piperidine (EM-MORPIP-MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazol carbocyanine). The EM-T-MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure-biological activity analyses.

CD133 suppression increases the sensitivity of prostate cancer cells to paclitaxel.

One of the major barriers in cancer therapy is the resistance to conventional therapies and cancer stem cells (CSCs) are among the main causes of this problem. CD133 as a CSC marker displays stem cell-like properties, tumorigenic capacity, and drug resistance in various cancers. However, the molecular mechanism behind CD133 function in prostate cancer (PC) still remains unclear. This research aimed to illustrate the probabilistic mechanism of CD133-siRNA and paclitaxel in the reduction of chemoresistance in PC cells. To measure the cell viability, migratory capacity, CSCs properties, invasive potential, apoptosis and cell cycle progression of the cells, the MTT, wound healing, spheroid assay, colony formation assay, DAPI staining and flow cytometry assays were applied in the LNCaP cell line, respectively. Also, quantitative real-time PCR (qRT-PCR) and western blot method were used for measuring the expression of CD133 and the effects of CD133 silencing on the AKT/mTOR/c-myc axis and pro-metastatic genes expression. We showed that the CD133-siRNA considerably decreased the CD133 expression. Moreover, CD133-siRNA and paclitaxel treatment significantly decreased cell proliferation and also inhibited the ability of cell migration and invasion and reduced pro-metastatic genes expression. Additionally, we found that the simultaneous use of CD133-siRNA and paclitaxel increased the paclitaxel-induced apoptosis. Our results confirmed that CD133 silencing combined with paclitaxel synergistically could suppress cell migration, invasion, and proliferation and enhance the chemosensitivity compared with mono treatment. Therefore, CD133 silencing therapy could be viewed as a promising and efficient strategy in PC targeted therapies.

Cell membrane-coated gold nanoparticles for apoptosis imaging in living cells based on fluorescent determination.

A nanoprobe was developed to achieve apoptosis detection by cell membrane-functionalized gold nanoparticles (AuNP-pep@Mem). The fluorescence of the fluorescein isothiocyanate isomer I (FITC)-labeled caspase-3 substrates was quenched by the attachment to AuNPs. The fluorescence signal was recovered via the cleavage of caspase-3 under apoptotic conditions. It exhibited a low detection limit of 1.3 pg·mL-1 with a linear range from 3.2 to 100 pg·mL-1 for caspase-3 detection with excitation wavelength of 490 nm. After wrapped by the cell membrane, the nanoprobe was effectively delivered into cells with high cell permeability. AuNP-pep@Mem nanoprobe provided signal enhancement of 1.8 times in living cells compared to non-membrane-coated nanoparticles (AuNP-pep). In combination with its excellent stability, low LOD and good specificity, the AuNP-pep@Mem probe can be an ideal probe for fluorescence imaging of apoptosis. Graphical abstractSchematic representation of fluorescent determination for apoptosis in living cells based on cell membrane-coated gold nanoparticls.

Aptamer-based colorimetric determination of early-stage apoptotic cells via the release of cytochrome c from mitochondria and by exploiting silver/platinum alloy nanoclusters as a peroxidase mimic.

An enzyme-free aptameric nanosensor is presented for apoptosis assay. The method exploits the peroxidase-mimicking property of silver/platinum alloy nanoclusters (Ag/Pt NCs) and uses a Cyt c binding ssDNA aptamer. An extra-strand polycytosine (C14) aptamer was designed as a template for synthesis of the Ag/Pt NCs. If cell lysate or purified Cyt c is placed in a polystyrene microplate, Cyt c will bind to the surface of the wells of a microtiterplate. On addition of Apt@Ag/PtNCs, it will associate with Cyt c and then catalytically oxidize colorless tetramethylbenzidine (TMB) in the presence of H2O2 to give a blue colored oxidation product (TMBox) due to the peroxidase-mimicking property of the Ag/Pt NCs. Under optimal conditions, the absorbance of TMB at 660 nm is linearly enhanced as the concentration of Cyt c increases from 50.0 fM to 500 nM, and the detection limit is ~10 pM. The assay is simple, sensitive and cost effective in that it is enzyme-free, antibody-free and label-free. Graphical abstractSchematic diagram of the apoptosis assay on the basis of microplate well-coated mitochondrial cytochrome c releasing by using Aptamer@Ag/Pt NCs.

A High Throughput Apoptosis Assay using 3D Cultured Cells.

A high throughput apoptosis assay using 3D cultured cells was developed with a micropillar/microwell chip platform. Live cell apoptosis assays based on fluorescence detection have been useful in high content screening. To check the autofluorescence of drugs, controls (no caspase-3/7 reagent in the assay) for the drugs are necessary which require twice the test space. Thus, a high throughput capability and highly miniaturized format for reducing reagent usage are necessary in live cell apoptosis assays. Especially, the expensive caspase-3/7 reagent should be reduced in a high throughput screening system. To solve this issue, we developed a miniaturized apoptosis assay using micropillar/microwell chips for which we tested seventy drugs (six replicates) per chip and reduced the assay volume to 1 µL. This reduced assay volume can decrease the assay costs compared to the 10-40 µL assay volumes used in 384 well plates. In our experiments, among the seventy drugs, four drugs (Cediranib, Cabozatinib, Panobinostat, and Carfilzomib) induced cell death by apoptosis. Those results were confirmed with western blot assays and proved that the chip platform could be used to identify high potency apoptosis-inducing drugs in 3D cultured cells with alginate.

Effects of New Generation All-Ceramic and Provisional Materials on Fibroblast Cells.

PURPOSE: The purpose of this in vitro study was to evaluate the cytotoxic and apoptotic effects of seven new-generation all-ceramic materials for CAD/CAM (Lava Ultimate [LU], VITA Mark II [VM], InCoris TZI [IC], IPS e.max CAD [EM], VITA Suprinity [VS], Cerasmart [CS], IPS Empress CAD [EC]) and six provisional materials (Protemp 4 [PT], Telio CAD [TC], CAD-Temp [CT], Telio Lab [TL], Temdent Classic [TD], Telio CS C&B [TS]) on L929 mouse fibroblast cells. MATERIALS AND METHODS: 24 disc-shaped specimens (∅ = 5 mm, h = 2 mm) were prepared from each test material. Medium extracts were collected at the 1st, 3rd, and 7th days for each group and tested using the L929 cell line. Cytotoxicity was evaluated using XTT assay, and apoptosis was determined by Annexin-V/PI staining. Data were analyzed using one-way ANOVA, Tukey's multiple comparison tests at a significance level of p < 0.05. RESULTS: The cell viability results among all-ceramic material groups after the 1st and 7th days of incubation periods showed statistically significant differences (p < 0.05). There were significant differences within the ceramic groups in different incubation periods regarding apoptosis rate (p < 0.05). Throughout the entire test period, LU and VM from the CAD/CAM all-ceramic materials and PT and TC from the provisional restoration materials showed cell viability higher than 90%. EC and TD showed the lowest cell viability and highest apoptosis rates in their own groups. For the provisional materials, there were significant differences in cell viability and apoptosis rate in all the incubation periods for each material (p < 0.05). CONCLUSIONS: Although some new-generation CAD/CAM and provisional restoration materials display slight cytotoxicity values, the results are still within the reliable range, and they can safely be used in clinical conditions.

Cytotoxicity of four denture adhesives on human gingival fibroblast cells.

OBJECTIVE: The purpose of this study was to compare the cytotoxicity of four denture adhesives on human gingival fibroblast cells. MATERIALS AND METHODS: Immortalized human gingival fibroblasts were cultured with one of four different denture adhesives, Polident, Protefix, Staydent or Denfix-A, which was placed in insert dishes (10% w/v concentration) for 48 h. The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and flow cytometric apoptosis assay were used to evaluate cell viability and apoptosis rates. The fibroblasts were also examined under a scanning electron microscope. RESULTS: The MTT assay showed that all denture adhesives resulted in a significantly lower cell viability compared to the control cells propagated in normal culture medium (p < 0.05), with Staydent demonstrating the lowest cell viability. According to the flow cytometric apoptosis assay, Staydent and Protefix showed significantly higher apoptosis rates than the control group (p < 0.05), whereas Polident and Denfix-A did not demonstrate any significant differences (p > 0.05). Staydent showed the highest apoptosis rate. Scanning electron microscopy showed that the cells of the Staydent group underwent cytoplasmic membrane shrinkage, with cell free areas containing residual fragments of the membrane of dead cells. CONCLUSIONS: The four denture adhesives evaluated in this study imparted cytotoxic effects on human gingival fibroblast cells. Staydent showed the highest toxicity.

Design, synthesis, and biological evaluation of novel quinoxaline aryl ethers as anticancer agents.

We designed and synthesized thirty novel quinoxaline aryl ethers as anticancer agents, and the structures of final compounds were confirmed with various analytical techniques like Mass, 1 H NMR, 13 C NMR, FTIR, and elemental analyses. The compounds were tested against three cancer cell lines: colon cancer (HCT-116), breast cancer (MDA-MB-231), prostate cancer (DU-145), and one normal cell line: human embryonic kidney cell line (HEK-293). The obtained results indicate that two compounds, FQ and MQ, with IC50 values < 16 µM, were the most active compounds. Molecular docking studies revealed the binding of FQ and MQ molecules in the active site of the c-Met kinase (PDB ID: 3F66, 1.40 Å). Furthermore, QikProp ADME prediction and the MDS analysis preserved those critical docking data of both compounds, FQ and MQ. Western blotting was used to confirm the impact of the compounds FQ and MQ on the inhibition of the c-Met kinase receptor. The apoptosis assays were performed to investigate the mechanism of cell death for the most active compounds, FQ and MQ. The Annexin V/7-AAD assay indicated apoptosis in MDA-MB-231 cells treated with FQ and MQ, with FQ (21.4%) showing a higher efficacy in killing MDA-MB-231 cells than MQ (14.25%). The Caspase 3/7 7-AAD assay further supported these findings, revealing higher percentages of apoptotic cells for FQ-treated MDA-MB-231 cells (41.8%). The results obtained from the apoptosis assay conclude that FQ exhibits better anticancer activity against MDA-MB-231 cells than MQ.

Nanofibers Embedded with Nanoparticles as Carriers for the Controlled Release of Anticancer Drug: Promoting the Apoptosis of Breast Cancer Cell Line and Growth Inhibition of Microbial Strains.

The polymeric nanofiber mats were produced from polylactic acid, methylcellulose, and polyethylene glycol with 5-fluorouracil (5Fu) drug and iron oxide (Fe3O4) nanoparticles. Spectral and crystallographic studies clearly elucidated the ionic interactions, structure and nature of the mats. Fe3O4 nanoparticles <10 nm in size, along with methyl cellulose and polyethylene glycol, have significantly reduced the size of nanofiber mats. The mechanical properties for the mats was found to be challenging; however, surface wettability, swelling capacity, and drug encapsulation efficiency results were promising. A controlled drug release pattern was observed from in vitro drug release study, zero-order kinetics, and a Higuchi model. Nanofiber mats showed higher anticancer activity (78%) against MDA-MB 231 cancer cells, which reveals that a small amount of 5Fu drug (15.86%) with high levels of O2••, H2O2, and OH• radicals generated from Fe3O4 have catalyzed the Fenton's reaction to eradicate the cancer cells, in a shorter span of 24 h, itself. In addition, the apoptosis assay by dual AO/PI staining method clearly exhibited the apoptotic cancer cells by fluorescence microscopy. Incorporation of Fe3O4 nanoparticles enhanced the anticancer activity of the mats, compared to the commercially available standard 5Fu drug. Nanofiber mats significantly controlled the growth of selected pathogenic microbial strains by the action of the 5Fu drug and Fe3+ ions. The degradation of mats was investigated by an in vitro mass loss study for a period of 360 days. In a nutshell, promising nanofiber mats were produced as targeted drug delivery devices for chemotherapy.

Wortmannin Inhibits Cell Growth and Induces Apoptosis in Colorectal Cancer Cells by Suppressing the PI3K/AKT Pathway.

BACKGROUND: Colorectal cancer (CRC) remains a significant contributor to mortality, often exacerbated by metastasis and chemoresistance. Novel therapeutic strategies are imperative to enhance current treatments. The dysregulation of the PI3K/Akt signaling pathway is implicated in CRC progression. This study investigates the therapeutic potential of Wortmannin, combined with 5-fluorouracil (5-FU), to target the PI3K/Akt pathway in CRC. METHODS: Anti-migratory and antiproliferative effects were assessed through wound healing and MTT assays. Apoptosis and cell cycle alterations were evaluated using Annexin V/Propidium Iodide Apoptosis Assay. Wortmannin's impact on the oxidant/antioxidant equilibrium was examined via ROS, SOD, CAT, MDA, and T-SH levels. Downstream target genes of the PI3K/AKT pathway were analyzed at mRNA and protein levels using RTPCR and western blot, respectively. RESULTS: Wortmannin demonstrated a significant inhibitory effect on cell proliferation, modulating survivin, cyclinD1, PI3K, and p-Akt. The PI3K inhibitor attenuated migratory activity, inducing E-cadherin expression. Combined Wortmannin with 5-FU induced apoptosis, increasing cells in sub-G1 via elevated ROS levels. CONCLUSION: This study underscores Wortmannin's potential in inhibiting CRC cell growth and migration through PI3K/Akt pathway modulation. It also highlights its candidacy for further investigation as a promising therapeutic option in colorectal cancer treatment.

Evaluation of BH3 mimetics as a combination therapy with irradiation in head and neck squamous cell carcinoma.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is a common cancer with a five-year survival rate around 60%, indicating a need for new treatments. BH3 mimetics are small molecules that inhibit anti-apoptotic Bcl-2 family proteins, resulting in apoptosis induction. METHODS: We performed a high-throughput screen using a Myogel matrix to identify the synergy between irradiation and the novel BH3 mimetics A-1155463, A-1331852, and navitoclax in 12 HNSCC cell lines, normal (NOF) and cancer-associated fibroblasts (CAF), and dysplastic keratinocytes (ODA). Next, we examined synergy in an apoptosis assay, followed by a clonogenic assay and a Myogel spheroid on selected HNSCC cell lines. Finally, we applied zebrafish larvae xenograft to validate the effects of navitoclax and A-1331852. RESULTS: All three BH3 mimetics exhibited a strong synergy with irradiation in eight HNSCC cell lines and ODAs, but not in NOFs and CAFs. A-1155463 and A-1331852 induced apoptosis and reduced proliferation, and together with irradiation, significantly increased apoptosis and arrested proliferation. A-1331852 and navitoclax significantly decreased the clonogenicity compared with the control, and combination treatment led to a decreased clonogenicity compared with monotherapy or irradiation. However, unlike navitoclax or A-1155463, only A-1331852 significantly reduced cancer cell invasion. Furthermore, in spheroid and zebrafish, irradiation appeared ineffective and failed to significantly increase the drug effect. In the zebrafish, A-1331852 and navitoclax significantly reduced the tumor area and metastasis. CONCLUSIONS: Our findings encourage the further preclinical investigation of BH3 mimetics, particularly A-1331852, as a single agent or combined with irradiation as a treatment for HNSCC.

Development of Piperazine- and Oxazine-Linked Pyrimidines as p65 Subunit Binders of NF-κB in Human Breast Cancer Cells.

Nuclear factor kappa B (NF-κB) is a potential therapeutic target in breast cancer. In the current study, a new class of oxazine- and piperazine-linked pyrimidines was developed as inhibitors of NF-κB, overcoming the complexity of the oxazine structure found in nature and enabling synthesis under laboratory conditions. Among the series of synthesized and tested oxazine-pyrimidine and piperazine-pyrimidine derivatives, compounds 3a and 5b inhibited breast cancer cell (MCF-7) viability with an IC50 value of 9.17 and 6.29 µM, respectively. In silico docking studies showed that the pyrimidine ring of 3a and the 4-methoxybenzyl thiol group of 5b could strongly bind the p65 subunit of NF-κB, with the binding energies -9.32 and -7.32 kcal mol-1. Furthermore, compounds 3a and 5b inhibited NF-κB in MCF-7 breast cancer cells. In conclusion, we herein report newer structures that target NF-κB in BC cells.

Chitosan nanoparticles as a smart nanocarrier for gefitinib for tackling lung cancer: Design of experiment and in vitro cytotoxicity study.

Due to its poor solubility and systemic side effects, gefitinib (Gef) has limited application in treatment of lung cancer. In this study, we used design of experiment (DOE) tools to gain the necessary knowledge for the synthesis of high-quality gefitinib loaded chitosan nanoparticles (Gef-CSNPs) capable of delivering and concentrating Gef at A549 cells, thereby increasing therapeutic effectiveness while decreasing adverse effects. The optimized Gef-CSNPs were characterized by SEM, TEM, DSC, XRD, and FTIR analyses. The optimized Gef-CSNPs had a particle size of 158±3.6 nm, an entrapment efficiency of 93±1.2 %, and a release of 97±0.6 % after 8 h. The in vitro cytotoxicity of the optimized Gef-CSNPs was found to be significantly higher than pure Gef (IC50 = 10.08 ± 0.76 µg/mL and IC50 = 21.65 ± 0.32 µg/mL), respectively. In the A549 human cell line, the optimized Gef-CSNPs formula outperformed pure Gef in terms of cellular uptake (3.286 ± 0.12 µg/mL and 1.777 ± 0.1 µg/mL) and apoptotic population (64.82 ± 1.25 % and 29.38 ± 1.11 %), respectively. These findings explain why researchers are so interested in using natural biopolymers to combat lung cancer, and they paint an optimistic picture of their potential as a promising tool in the fight against lung cancer.

Green Fabrication of silver nanoparticles by leaf extract of Byttneria Herbacea Roxb and their promising therapeutic applications and its interesting insightful observations in oral cancer.

The present research was carried out to look into therapeutic insight of biosynthesized silver nanoparticles (AgNPs) by leaf extract of Byttneria herbacea Roxb (BH). The analysis of biosynthesized BH-AgNPs by UV-visible spectroscopy shows an intense surface plasmon resonance (SPR) peak at 422 nm initially and 437 nm after 30 min which certainly reveals the formation of BH-AgNPs. Fourier Infra-red Spectroscopy (FT-IR) reveals that BH-AgNPs are biosynthesized by using different bioactive compounds like O-H stretch of free hydroxyl alcohol and phenols, N-H bond of primary amines present in the leaf extract. Transmission Electron Microscope (TEM) analysis revealed that BH-AgNPs are almost spherical in nature with an average size range from of 2 nm to 12 nm. The particle size analysis by Dynamic Light Scattering (DLS) reveals that the BH-AgNPs are poly-dispersed in nature with an average size of 8 nm ± 2 nm, with a negative zeta potential value of -21 mV which reveals the biosynthesized BH-AgNPs are very stable. The BH-AgNPs (Byttneria herbacea -AgNPs) revealed excellent free radical scavenging activity and exceptional antimicrobial activity. The anti-proliferative and cytotoxic studies in KB oral cancer cells revealed biosynthesized BH-AgNPs can employ as future novel therapeutic agents in cancer treatment and other biomedical applications.

A Study on the Effect of Nanoscale MgO and Hydrogen Bonding in Nanofiber Mats for the Controlled Drug Release along with In Vitro Breast Cancer Cell Line and Antimicrobial Studies.

Nanosized metal oxide-incorporated drug carriers have received significant attention due to their biocompatibility, mechanical strength, controlled drug release, and biodegradability. Herein, an attempt was made to fabricate polycaprolactone-based electrospun nanofiber mats involving the 5-fluorouracil (5Fu) drug, MgO nanoparticle, methyl cellulose, and polyethylene glycol. The chemical interactions, surface wettability, mechanical properties, structural and morphological changes, and thermal stability were studied by the respective analyses. The ionic interaction between 5Fu, MgO, and polymers were found to be responsible for the controlled drug release. Zero-order kinetic and model data also revealed that a controlled drug release pattern was observed in a period of 16 days. Furthermore, the nanofiber mats were subjected to cytotoxicity studies against MDA-MB-231 cancer cell line and the results showed higher cytotoxicity in a short time of 24 h and less toxicity to normal L929 fibroblast cell line. The apoptosis in cancer cell lines was also tested by AO/PI staining assay and confirmed by fluorescence microscopy. In addition, the growth inhibition of several bacterial and fungal strains was tested for the mats and the results exhibited good inhibition activity. Hence, the reported nanofiber drug carrier was found to be an efficient implant for the controlled release of anticancer drug along with other significant properties.

Discovery of potential novel CRBN modulators by virtual screening and bioassay.

The incidence of malignant tumor with high mortality is increasing yearly. CRBN E3 ubiquitin ligase was proved to be an antitumor target. It was found that thalidomide and its analogs could bind to CRBN E3 ubiquitin ligase and modulate CRBN. CRBN modulators could promote the binding of CRBN to specific target proteins or block the binding of CRBN to some endogenous proteins. In this way, CRBN modulators suppress various tumor cells by modulating the interactions between CRBN and various antitumor target proteins. However, almost all CRBN modulators reported include glutarimide scaffold. Therefore, the aim of this study is to developed novel CRBN modulators. Virtual screening methods and bioassay methods, including structural similarity search, molecular docking, substructure search, antitumor evaluation and apoptosis assay were used to search novel potential CRBN modulators in Specs database. Finally, 15 compounds exhibited strong inhibition activity against A549 cells. Among these active compounds, The IC50 value against A549 of AG6033 was 0.853 ± 0.030 µM. Apoptosis assay demonstrated that AG6033 could promote apoptosis of A549 cells. Further mechanism studies suggested that AG6033 caused remarkable decrease of GSPT1 and IKZF1, the substrates of CRBN, and AG6033 induced cytotoxic effects was CRBN-dependent.

Biofabrication of Silver Nanoparticles (AgNPs) Using Embelin for Effective Therapeutic Management of Lung Cancer.

Nanobiotechnology is a burgeoning field of research with applications in cancer treatment, targeted chemotherapy, and molecular diagnosis. This study aims at the fabrication of silver nanoparticles using embelin derived from Embelia ribes to evaluate its anticancer property. Silver nanoparticles (AgNPs) have emerged as a novel nano-carrier for therapeutic agents with a wide range of medical capabilities due to their unique structural, physicochemical, and optical features. In our study, the particle size of fabricated AgNPs was measured as 25 nm, and the zeta potential was recorded as -5.42 mV, which indicates the good stability of embelin-derived AgNPs. The crystalline surface morphology was observed by SEM analysis. The FT-IR spectrum confirmed the reduction in silver ions (Ag+) by embelin, and the TEM analysis exhibited polydispersed Ag+ of 20-30 nm. The anticancer potential of embelin-fabricated AgNPs was investigated using in vitro studies on lung cancer cells by the MTT assay. The results revealed significant dose-dependent inhibition of cell proliferation against A549 cell lines. Embelin AgNP-induced apoptosis was measured by the annexin-V PI apoptosis assay, which exhibited significantly low necrotic cells as compared to apoptotic cells. Finally, the findings of our study suggest the anticancer potential of biofabricated embelin AgNPs, particularly against lung cancer cells.

Downregulation of HMGA2 by Small Interfering RNA Affects the Survival, Migration, and Apoptosis of Prostate Cancer Cell Line.

Purpose: To investigate the downregulation of high mobility group AT-hook 2 (HMGA2)expression by small interfering RNAs (siRNAs) in PC3 prostate cancer cell line. HMGA2belongs to the non-histone chromatin-binding protein family that serves as a crucial regulator ofgene transcription. The overexpression of this gene is positively correlated with various prostatecancer (PC)-related properties. Thus, HMGA2 is an emerging target in PC treatment. This studyaimed to examine the impact of siRNAs targeting HMGA2 on the viability, migration, andapoptosis processes of the PC3 PC cell line. Methods: siRNA transfection was conducted with a liposome-mediated approach. The mRNAand protein expression levels for HMGA2 are evaluated by real-time polymerase chain reaction(qRT-PCR) and western blot analysis. The cytotoxic properties of HMGA2-siRNA were measuredby MTT assay on PC3 cells. The migration of PC3 cells was measured by implementing awound-healing assay. Apoptosis measurement was also quantified by TUNEL assay. Results: Transfection with siRNA significantly decreased both mRNA and protein levels of theHMGA2 gene in a dose-dependent manner after 48 hours. Also, we demonstrated that theknockdown of HMGA2 led to a reduction in cell viability, migration ability, and enhancedapoptosis of PC3 cells in vitro. Conclusion: Our findings recommend that the specific siRNA of HMGA2 may efficiently beable to decrease PC progression. Therefore, it may be a promising adjuvant treatment in PC.