Colorectal Carcinoma Cells Research Articles

Novel Pyrrolo-Pyrimidine Derivatives Bearing Amide Functionality as Potential Anticancer Agents: Synthesis and Molecular Docking Studies

Current investigation presents the synthesis, molecular docking and anticancer evaluation of novel pyrrolo-pyrimidine derivatives designed to target Janus kinase 1 (JAK1), Janus kinase 2 (JAK2) and cyclin-dependent kinase 4 (CDK4). The synthesis route commenced with 2-amino-4,6-dichloropyrimidine-5-carbaldehyde, proceeding through sequential steps involving intermediate formations and coupling reactions to yield a diverse array of pyrrolo-pyrimidine derivatives. Characterization using spectroscopic techniques (1H NMR, 13C NMR and HRMS) confirmed the chemical structures of the synthesized compounds. Molecular docking studies against JAK1, JAK2 and CDK4 demonstrated substantial binding affinities, remarkably compounds 7k, 7l and 7d, which displayed promising interactions within the active sites of the proteins. Anticancer evaluation against breast cancer (MCF-7), chronic myeloid leukemia (SET-2), colorectal carcinoma (HCT-116) and HEK-293 cell lines revealed diverse cytotoxic profiles. Specifically, compounds 7k and 7f exhibited potent activity against breast cancer (MCF-7), 7k and 7f showed efficacy against chronic myeloid leukemia (SET-2) and compounds 7k and 7l demonstrated effectiveness against colorectal carcinoma (HCT-116). These findings underscore the potential of these pyrrolo-pyrimidine derivatives as selective and effective anticancer agents, prompting further exploration for therapeutic development.

AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway.

Colorectal cancer remains a significant cause of mortality worldwide. A spiro-acridine derivative, (E)-1'-((4-bromobenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-19), showed significant cytotoxicity in HCT-116 colorectal carcinoma cells (half maximal inhibitory concentration, IC50 = 10.35 ± 1.66 µM) and antioxidant effects after 48 h of treatment. In this study, Molegro Virtual Docker v.6.0.1 software was used to investigate the interactions between AMTAC-19 and the Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), and p38 Mitogen-Activated Protein Kinase α (p38α MAPK). In vitro assays were conducted in HCT-116 cells to evaluate the effect of AMTAC-19 on the modulation of these proteins' activities using flow cytometry. Furthermore, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in the presence or absence of ERK1/2, JNK, and p38 MAPK inhibitors was used to evaluate the involvement of these enzymes in AMTAC-19 cytotoxicity. ROS production was assessed using the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay at various incubation times (30 min, 1 h, 6 h, 12 h, and 24 h), and the MTT assay using N-acetyl-L-cysteine (NAC) was performed. In silico results indicated that AMTAC-19 interacts with ERK1, JNK1, and p38α MAPK. Additionally, AMTAC-19 activated ERK1/2 and JNK1 in HCT-116 cells, and its cytotoxicity was significantly reduced in the presence of ERK1/2 and JNK inhibitors. AMTAC-19 also induced a significant increase in ROS production (30 min and 1 h), while NAC pretreatment reduced its cytotoxicity. These findings support AMTAC-19's in vitro antitumor effect through ROS-dependent activation of ERK and JNK pathways.

Colorectal carcinoma progression is not influenced by the pseudokinase PEAK1

The scaffold protein PEAK1 acts downstream of integrin adhesion complexes and the epidermal growth factor receptor, orchestrating signaling events that control cell proliferation and cytoskeletal remodeling. In this study we investigated the role of PEAK1 in colorectal carcinoma (CRC) progression using various in vitro and in vivo models to replicate the stepwise pathogenesis of CRC. While we observed a cell-type specific role for PEAK1 in the proliferation and in human CRC cell lines in vitro, our in vivo experiments using different CRC mouse models driven by loss of Apc, with or without oncogenic Kras or Pten loss suggest that PEAK1 does not significantly contribute to tumor formation in vivo. However, the survival time of Peak1−/− mice in the Apcfl/+ model appeared to be slightly increased. Furthermore, PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization and lumenization. Given that the Caco-2 cells harbor mutations in the tumor suppressors APC and β-CATENIN, but not in other tumor suppressors or in proto-oncogenes, we conclude that the PEAK1’s impact on colon carcinogenesis is limited, potentially playing a role in the initial stage of the adenoma to carcinoma progression.

Colorectal carcinoma-induced iron deficiency anemia: A literature review and a case scenario

Colorectal carcinoma (CRC) is among the leading cancers worldwide and a major cause of cancer-related mortality. Iron deficiency anemia (IDA), resulting from inadequate iron for hemoglobin production, has been increasingly linked to CRC, often leading to misdiagnosis. This study reviews the clinicopathological associations of IDA in the context of colorectal cancer, using the medical records of a septuagenarian diagnosed with both conditions as a case study. Employing the Problem-Intervention-Comparison-Outcome model, we searched for “colorectal carcinoma” and “iron deficiency anemia” as keywords. CRC ranks among the top five cancers of global health importance, with socioeconomic factors, sedentary lifestyles, and dietary choices significantly influencing both conditions. Notably, IDA is particularly associated with the right-sided CRC in individuals over 40. Upregulation of interleukin-6 in CRC cells stimulates hepcidin release, which mediates anemia of chronic disorders and IDA. The case revealed right-sided signet ring cell CRC, microcytic hypochromic anemia, bone marrow metastasis, and low serum iron and ferritin levels. This study highlights the need for increased suspicion of CRC in middle-aged and elderly patients presenting with recurrent IDA. Regular screening is essential for the early detection and improved treatment outcomes. While colonoscopy is the gold standard for prevention, its effectiveness in detecting early molecular links between neoplasia and chronic inflammation is limited. There is also no consensus on surveillance protocols, and many gastroenterologists do not adhere to recommended biopsy sampling practices. In conclusion, this study advocates for including complete blood count and iron studies as essential tests in guidelines for screening and diagnosis for CRC-related IDA to enhance diagnostic practices.

Ascorbic acid regulates in vitro and in vivo toxicogenetic effects of hydroxyurea on eukaryotic cells

Hydroxyurea (HU) exerts unique and diverse biological effects as an anti-leukemic agent, irradiation sensitizer, and HbS inducer in patients with sickle cell anemia. Herein, we assessed the potential toxicogenic and/or oxidant effects of hydroxyurea associated with ascorbic acid by in vivo examinations in Allium cepa and human cancer cells and systemically on mice tissues. Growing A. cepa roots and HCT-116 colorectal tumor cells were examined after HU and HU plus ascorbic acid exposure. DNA damage and antioxidant enzymatic activity were quantified in peripheral blood mononuclear cells (PBMC), bone marrow leukocytes and livers of mice after 7 day-HU treatment (7.5, 15 and 30 mg/kg/day) and Vitamin C 2 μM. Hydroxyurea presented toxic effects on meristematic Allium cepa cells, causing chromosomal abnormalities and reduction of mitotic index, killed HCT-116 colorectal carcinoma cells and induced DNA injuries upon mice cells (hepatocytes, bone marrow leukocytes and PBMC). Simultaneously, hydroxyurea decreased levels of CAT and GSH activities and expand lipid peroxidation. All these biochemical and physiological changes were ameliorated when associated with ascorbic acid, indicating it restored antioxidant enzymes, decreased MDA levels, removed peroxides and, consequently, presented cytoprotection against HU-provoked cellular damage in normal cells. On the other hand, antioxidants compounds may interfere on effectiveness of HU during anticancer chemotherapies.

Tumor Differentiation is Correlated with Estrogen Receptor Beta (ERβ) Expression but Not with Interleukin-6 (IL-6) Expression in Colorectal Carcinoma

BACKGROUND: Colorectal carcinoma (CRC), the third most common malignant disease worldwide, is associated with estrogen receptor β (ERβ) and interleukin-6 (IL-6). ERβ is known to down-regulate IL-6 in prostate cancer, lung carcinoma, and CRC cell lines; however, its effect on human with CRC remains unclear. Therefore, this study was conducted to investigate the association between ERβ and IL-6 expressions with the clinicopathological features of CRC.METHODS: This was an analytic observational study using 40 paraffin blocks of CRC patients. ERβ and IL-6 expression was measured by immunohistochemistry (IHC) staining. The percentage of immunoreactive tumor cell per 1000 cells was manually recorded and tumor differentiation as well as tumor infiltration were determined. Tumor differentiation was graded according to the World Health Organization (WHO) 2010 criteria, while tumor infiltration was defined based on the American Joint Committee on Cancer (AJCC) 8th edition.RESULTS: Fifty percent of samples were well-differentiated CRC, and 57.5% samples were T3 infiltration tumors. IHC staining showed 35.5% of samples were positive for ERβ expression, while 70.86% were positive for IL-6 expression. There were negative correlation of ERβ expression with tumor differentiation (p=0.018; r=-0.371), but no correlation with tumor infiltration (p=0.836) were found. There was no correlation between ERβ expression with IL-6 expression (p=0.154).CONCLUSION: There is statistically significant correlation between tumor differentiation and ERβ expression, wherein improved tumor differentiation is linked to higher levels of positive ERβ expression. However, there is no discernible relationship between IL-6 and tumor differentiation. These findings suggest that while IL-6 was involved in the growth of the tumor, ERβ expression might have an impact on tumor differentiation.KEYWORDS: colorectal carcinoma, estrogen receptor beta, interleukin-6, cell differentiation

Food grade titanium dioxide induced endoplasmic reticulum stress in colon cells: Comparison between normal and colorectal carcinoma cells

BackgroundFood-grade titanium dioxide (E171) has been under scrutiny in the last decade since its possible adverse effects; however, the cellular mechanisms underlying E171 toxicity have not been thoroughly described. AimWe aimed to compare the effects of E171 on endoplasmic reticulum (ER) homeostasis in normal and cancer colon cells. Experimental designWe exposed normal, carcinoma, and adenocarcinoma cells to 0.1, 1, 10, 50 and 100 μg/cm2 of E171 for 24, 48 and 72 h, and we evaluated ER stress, cell viability, titanium uptake, intracellular calcium concentration, and gene expression related to unfolded protein response (UPR) and chaperone pathways. ResultsCell viability decreased only after 72 h of exposure to 100 μg/cm2 of E171. Adenocarcinoma cells internalized higher titanium amounts than normal and carcinoma cells, but the effects in ER distribution, intracellular calcium concentration, and gene expression were similar among the three cell lines. The expression of UPR and chaperone pathways were downregulated at the lowest concentrations but upregulated at the highest concentrations in the three cell lines. ConclusionE171 induces ER stress through alterations in ER distribution, intracellular calcium, and UPR and chaperone protein pathways.

Isoxazole based nucleosides induce autophagy through the production of ROS and the suppression of the β-catenin pathway in human colorectal carcinoma cells

β-catenin is frequently implicated in signaling pathways that regulate autophagy, and the production of reactive oxygen species (ROS) has been linked to autophagy activation. Isoxazole-based nucleoside compounds have demonstrated anti-cancer properties. In this study, we report the identification of novel isoxazole-nucleosides as anti-tumor agents and their impact on autophagy in human colorectal carcinoma (CRC) cells. Among the ITP series, ITP-7 and ITP-9 (ITP-7/9) exhibited significant cytotoxicity compared to other compounds. Treatment with ITP-7/9 upregulated the expression of key autophagy-related proteins, including LC3 II, Atg7, and phosphorylated Beclin-1. Additionally, ITP-7/9 promoted the formation of LC3 II puncta and increased the number of AO-stained and MDC-stained cells, indicating enhanced autophagy. ROS levels were elevated following ITP-7/9 exposure, and treatment with N-acetyl l-cysteine (NAC), a ROS inhibitor, reduced the ITP-7/9-induced expression of LC3 II. Furthermore, ITP-7/9 inhibited β-catenin's role as a transcription factor, as observed in ICC assays. Moreover, cells with β-catenin gene deletion exhibited stronger autophagy when treated with ITP-7/9 compared to those treated with ITP-7/9 alone. These findings suggest that ITP-7/9 induces autophagy and promotes CRC cell death by downregulating β-catenin.

Formulation and characterization of 5-fluorouracil and metformin biodegradable nanospheres for treating colon cancer

BackgroundCancer and diabetes mellitus are quite common diseases found together worldwide. A considerable amount of evidence is available for the rapid development and presentation of various types of cancer in the type 2 diabetes mellitus (DM2) population as compared with the population without diabetes. The objective of the study is to formulate and evaluate 5-fluorouracil (5-FU) and metformin (MET) nanoparticles (NPs) and to establish the characteristic features of the biodegradable NPs. 5-FU and MET NPs with chitosan as a biodegradable polymer were formulated by the ionotropic cross-linking method. 0.25 gm of MET and 0.25 gm of 5-FU were dissolved in 100 ml of distilled water, and stock solution was prepared. 5 ml of stock solution was slowly mixed into the chitosan solution to obtain the mixture of drugs and chitosan. The tripolyphosphate reserve liquid was dripped slowly into the chitosan solution with constant stirring until the opaline appearance was noticed in the mixture, then filtered, and dried. The NPs were evaluated for their physical properties and drug release kinetics. Cell proliferation assay was done using human colorectal carcinoma cell line (HCT 116).ResultsThe formulation composed of 1.5 w/v of chitosan, 0.25 w/v of MET, and 5-FU had an average particle diameter of 198.7 nm. The polydispersity index was 0.757. Thermal and infrared spectroscopy results indicated the drugs and polymers selected for the formulation were unique without any identifiable interaction. The NPs were spherical in appearance, with numerous pours on the surface, which was evident when microscopically examined. Uniformity in drug release was observed, and the formulation demonstrated excellent release kinetics. HTC 116 cell line confirmed that the maximum percentage of cell death and minimum viability of cells were observed while using the combination of MET and 5-FU-NPs as compared to the pure MET or 5-FU alone.ConclusionMET and 5-FU-loaded chitosan NPs were found to have excellent physiochemical properties, particle size, and drug release from the polymer in a controlled manner. Half-maximal inhibitory concentration value (IC50) of MET and 5-FU-NPs was found to be significantly less as compared to MET and 5-FU alone or the combination.

Design and Development of [1,2,4]Triazolo[4,3-b][1,2,4]triazines as Potential Anticancer Agents with Genotoxicity and Apoptotic Activity

Aims: In this current study, a new series of triazolo-triazine derivatives were designed and synthesized as potential anticancer agents. Methods: The antiproliferative activity of the new compounds was evaluated against three different cancerous cell lines (MDA-MB-231, HCT-116, A549, and HT-29) using an MTT assay. To evaluate the mechanism of action, the ability of the best compound in apoptosis induction and DNA damage was evaluated using the flow cytometry technique and comet assays. Furthermore, molecular docking simulation was used to investigate their interactions with the two targets, VEGFR2 and c-Met kinases. Results: Results showed that 6-(4- bromophenyl)-3-((4-methoxybenzyl)thio)-[1,2,4]triazolo[4,3-b][1,2,4]triazine (8c) demonstrated the best anti-proliferative activity against the human colorectal carcinoma cells HCT-116 with an IC50 value of 38.7 ± 1.7 μM. In silico evaluations showed that the triazolo-triazine scaffold, along with the methoxy substitution of compound 8c, was involved in creating effective H-bond interactions in the active site of both targets. Conclusion: Our results showed that compound 8c significantly increased cell death through apoptosis induction and caused a significant increase in genotoxicity. Furthermore, it was found that the tested compound 8c, with a selectivity index of 1.74, possessed selective antiproliferative activity towards the colorectal cancer cell line HCT-116 compared to the normal fibroblast cell line. These findings could be useful in the development of novel VEGFR2/c-Met dual-targeted inhibitors in the future.

Effect of N-substituted aliphatic glycine presence on bioactivity, cytotoxicity, and selectivity of Pt(II) and Pd(II) complexes in cancer treatment

In this study, four new platinum (II) and palladium(II) complexes were synthesized to develop metallo-drugs that can attach to DNA and prevent the division of cancer cells. The complexes, 1: [Pt(bipy)(LP)]NO3, 2: [Pt(bipy)(LA)]NO3, 3: [Pd(bipy)(LP)]NO3, and 4: [Pd(phen)(LP)]NO3 (where LP is propylglycine, LA is 2-heptyl glycine, bipy is 2,2-bipyridine, and phen is 1,10-phenanthroline), were structurally characterized using computational and experimental analysis. Their stability, solubility, and lipophilicity were evaluated. Single-crystal X-ray and powder X-ray crystallographic analyses were performed for [Pt(bipy)(LA)]NO3. Density functional theory calculations were performed to investigate the reactivity, stability descriptors, and natural bond orbital analysis of these complexes. The in vitro cytotoxicity of these substances was examined against the human colorectal carcinoma (HCT116), A549 (Human Caucasian lung carcinoma), MCF7 (breast cancer), and HFF (Human Freskin Fibroblast) cell lines. According to the findings, complexes 4 and 3 had near oxaliplatin concentrations and more than carboplatin due to lipophilic ligands in their structure. Also, regarding IC50 values on normal HFF cell line, 4 is selectively toxic against the A549 cancer cell line with SI=5.6. Fluorescence, electronic absorption spectroscopy, and CD spectroscopy were used to investigate the binding affinities of compounds to CT-DNA and HSA. The results revealed that they could interact with CT-DNA through groove mode and with HSA via hydrogen bond and van der Waals forces. Electronic absorption and CD spectra indicated that compounds changed the way the HSA folded by increasing the proportion of a-helix. The binding posture of the metal complex to both biomolecules was predicted using docking simulation, which also verified the groove binding for DNA-complex. The findings indicated that complex 4 had a greater negative docking energy and a higher propensity for CT-DNA and HSA interaction.

Uncovering the Potential of Chalcone-Sulfonamide Hybrids: A Systematic Review on Their Anticancer Activity and Mechanisms of Action.

Cancer is the second leading cause of death worldwide and is considered a major public health problem. Despite the significant advances in cancer research, the conventional cancer treatment approaches often lead to serious side effects that affect the quality of life of cancer patients. Thus, searching for new alternatives for cancer treatment is crucial to minimize these problems. Chalcone-sulfonamide hybrids display a range of biological activities and have been widely investigated for their anticancer potential, being considered promising molecules for cancer treatment. This systematic review aimed to summarize the information available in the literature about the anticancer potential of chalcones-sulfonamides in vitro and in vivo and their mechanisms of action. Our analysis demonstrated that chalcones-sulfonamides have relevant cytotoxic potential against different cancer cell lines in vitro, especially against the human colorectal carcinoma cell line HCT-116. These molecules have also reduced tumor growth in vivo. Some chalcones-sulfonamides had improved cytotoxicity after chemical modification and could become more selective or even more potent than reference chemotherapeutics. The mechanisms underlying these effects demonstrated that chalcones-sulfonamides may lead to cell death by different pathways, predominantly via apoptosis or necroptosis. This review may encourage researchers to advance studies with chalcones-sulfonamides, especially to elucidate their mechanisms of action, contributing to the development of new alternatives to cancer treatment.

5,10,15,20-Tetrakis(4-sulfonatophenyl)porphyrin Zinc and Chloro-aluminum Phthalocyanine Disulfonate in Photodynamic Therapy of Colorectal Adenocarcinoma In Vitro.

Colorectal cancer (CRC) is one of the most widespread malignancies. One of the alternative therapeutic methods appears to be photodynamic therapy (PDT). This study investigated the efficiency of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin zinc (ZnTPPS4) and chloro-aluminum phthalocyanine disulfonate (ClAlPcS2) with two commercial photosensitive compounds 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP) and tetramethylthionine chloride (methylene blue, MB) in PDT for CRC in vitro. In addition to the study of the photodynamic effect on the viability of the colorectal carcinoma cell line HT29, cellular uptake, ROS production, and DNA damage were investigated. All photosensitizers showed good accumulation within HT29 cells, high efficiency in killing the cells, and a concentration-dependent increase in the production of ROS. PDT using ZnTPPS4 and ClAlPcS2 may be effective in the treatment of CRC, achieving a similar photocytotoxic effect at much lower concentrations compared to MB.

Fusobacterium Nucleatum Promotes Microsatellite Instability in Colorectal Carcinoma Through Up-regulation of miRNA-155-5p-Targeted Inhibition of MSH6 via the TLR4/NF-κB Signaling Pathway.

Fusobacterium nucleatum (Fn) is significantly associated with poor prognosis in colorectal carcinoma (CRC), however, mechanisms of Fn in DNA mismatch repair (MMR) and microsatellite instability (MSI) in CRC have not been fully elucidated. Clinical samples are collected to analyze the relationship between Fn abundance and microsatellite stability. Tumor cells are treated with Fn to detect the expression of proteins related to toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88), mutS homolog 6 (MSH6), and nuclear factor-κB (NF-κB) signaling pathways, respectively. Combined with the prediction results from TargetScan, the regulatory role of microRNA upstream of MSH6 is demonstrated. The effect of this regulatory axis on CRC development is demonstrated using a nude mouse tumor model. Compared with microsatellite stability (MSS)-type CRC patients, MSI-type showed higher Fn abundance. Fn treatment of CRC cells activated TLR4/Myd88/NF-κB signaling pathway, transcriptionally activating miRNA-155-5p expression, thereby negatively regulating MSH6. Fn treatment accelerated the malignant progression of CRC in mice, and this process is inhibited by miRNA-155-5p antagomir. Fn in CRC upregulated miRNA-155-5p by activating TLR4/NF-κB signaling to inhibit MSH6, and this regulatory pathway may affect MSS of cancer cells.

Synthesis, cytotoxic evaluation, and in silico studies of novel benzenesulfonamide-thiazolidinone derivatives against colorectal carcinoma

Thirteen new benzenesulfonamide derivatives containing 4-thiazolidinone were synthesized. Their cytotoxic properties were tested on colorectal carcinoma (HT-29, DLD-1, COLO-205) and normal colon fibroblast (CCD-986Sk) cell lines. Compounds 3l (IC50=114.62 µM), 3a (IC50=25.82 µM), 3k (IC50=30.99 µM), and 3i (IC50=62.94 µM) showed the highest cytotoxicity on HT-29, DLD-1, COLO-205, and CCD-986Sk cell lines, respectively. Compound 3e (IC50=1075.4 µM) exhibited the least cytotoxicity against CCD-986Sk. The apoptosis profile of 5-FU at 5 µM was similar to that of compound 3e at 30 µM. Molecular docking and MD simulations showed stable interactions for compounds 3i and 3e. Molecular docking and MD simulations revealed that compounds 3i and 3e exhibit stable interactions with key cancer-related protein targets, particularly TGFβ2. These interactions suggest their potential as therapeutic agents. The predicted ADME parameters further highlighted compounds 3e and 3i for their favorable lipophilicity, solubility, permeability, and oral absorption profiles, supporting their promise as candidates for future drug development.

Synthesis, anticancer activity, docking and computational studies of new pyridyl-glycosyl hybrids and acyclic analogs.

New pyridine-O-glycosides and their acyclic nucleoside analogues were prepared by heterocyclization and glycosylation. The anticancer activity against HCT-116, HepG2 and MCF-7 human cancer cells and BJ-1 cell revealed that the galacto- and xylopyranosyl glycosides possessing 4-bromophenyl have superior cytotoxic activities against HepG2 cell while glycosides 7-9 resulted in superior cytotoxic activities regarding MCF-7 breast cell. In case of HCT-116 colorectal carcinoma cells, two products and the derived glycosides and acyclic analogues showed potent activities. The most potent compounds were investigated for their possible binding affinities to the active site of CDK2 enzyme via in silico molecular docking simulation in addition to computational studies. The results support the antiproliferative effect and elucidate the interactions of 3a and 8 with catalytic sites.

Microwave synthesis, density functional theory study and antiproliferative activity of the novel spiropyrazole derivatives

Different spiro-pyrazole-oxy-indoline substituted compounds I-IV have been synthesized. In Jaguar, Hybrid DFT using Becke’s three-parameter transfer possibility also,Lee-Yang-Parr correlated practical (B3LYP) viewwith a 6-31 G** basis set were utilized to improve the geometrical characteristics of the hit molecules and reference compound. The MTT test exhibited whether the prepared substance has an inhibitory impact on cell development or not. This was successfully represented that in hepatocellular carcinoma (HEPG-2), colorectal carcinoma (HCT-116), and mammary gland breast cancer cell lines (MCF-7) colorimetric test, the mitochondrial succinate dehydrogenase in live cells transform yellow tetrazolium bromide (MTT) to a purple formazan product. Compound IV was found to be a better cytotoxic action against to the HEPG-2 hepatocellular carcinoma cell line, and it has been seen a strong activity against the colorectal carcinoma cell lines HCT-116 and MCF-7 mammary gland breast cancer cell lines. While the other three compounds I, II, and III showed a moderate cytotoxic action to high action against the same cell lines.

Signal-amplified detection of amyloid-β aggregates based on plasmon-enhanced fluorescence

Protein aggregation and misfolding are the main causes of neurodegenerative diseases. The development of a sensitive detection method and early diagnosis is significant for the prevention, diagnosis and treatment of these diseases. Herein, boron dipyrromethene (BODIPY)-modified probe based on plasmon-enhanced fluorescence (PEF) was developed for the detection of amyloid-β protein (Aβ) aggregates. Gold nanoparticles (Au NPs) and BODIPY were as the plasma, fluorescent substance, respectively. Meanwhile, the distance between the Au NPs and the BODIPY was controlled by silica spacer. Compared with the original BODIPY, the fluorescence signal of BODIPY-decorated Au NPs (Au NPs@SiO2-BODIPY) exhibited 13-fold fluorescence enhancement. Three dimensions finite difference time domain (3D-FDTD) result demonstrated the signal-amplified was ascribed to the increase of electric field intensity (3.78 V/m). The linear range and detection limit for Aβ42 detection were lowered to 5–60 μM and 0.85 μM. The developed PEF probe was applied to selective and sensitive recognize Aβ aggregates in mouse colorectal carcinoma cells (CT26) and mouse pancreatic cancer cells (PAN02), which also showed a higher fluorescent signal than the original BODIPY. This method has a broad application prospect in the prediction and detection of neurodegenerative diseases.

Novel Galectins Purified from the Sponge Chondrilla australiensis: Unique Structural Features and Cytotoxic Effects on Colorectal Cancer Cells Mediated by TF-Antigen Binding.

We here report the purification of a novel member of the galectin family, the β-galactoside-binding lectin hRTL, from the marine sponge Chondrilla australiensis. The hRTL lectin is a tetrameric proto-type galectin with a subunit molecular weight of 15.5 kDa, consisting of 141 amino acids and sharing 92% primary sequence identity with the galectin CCL from the congeneric species C. caribensis. Transcriptome analysis allowed for the identification of additional sequences belonging to the same family, bringing the total number of hRTLs to six. Unlike most other galectins, hRTLs display a 23 amino acid-long signal peptide that, according to Erdman degradation, is post-translationally cleaved, leaving an N-terminal end devoid of acetylated modifications, unlike most other galectins. Moreover, two hRTLs display an internal insertion, which determines the presence of an unusual loop region that may have important functional implications. The characterization of the glycan-binding properties of hRTL revealed that it had high affinity towards TF-antigen, sialyl TF, and type-1 N-acetyl lactosamine with a Galβ1-3 structure. When administered to DLD-1 cells, a colorectal carcinoma cell line expressing mucin-associated TF-antigen, hRTL could induce glycan-dependent cytotoxicity.

Chromosome instability functions as a potential therapeutic reference by enhancing chemosensitivity to BCL-XL inhibitors in colorectal carcinoma.

Chromosome instability (CIN) and subsequent aneuploidy are prevalent in various human malignancies, influencing tumor progression such as metastases and relapses. Extensive studies demonstrate the development of chemoresistance in high-CIN tumors, which poses significant therapeutic challenges. Given the association of CIN with poorer prognosis and suppressed immune microenvironment observed in colorectal carcinoma (CRC), here we aimed to discover chemotherapeutic drugs exhibiting increased inhibition against high-CIN CRC cells. By using machine learning methods, we screened out two BCL-XL inhibitors Navitoclax and WEHI-539 as CIN-sensitive reagents in CRC. Subsequent analyses using a CIN-aneuploidy cell model confirmed the vulnerability of high-CIN CRC cells to these drugs. We further revealed the critical role of BCL-XL in the viability of high-CIN CRC cells. In addition, to ease the evaluation of CIN levels in clinic, we developed a three-gene signature as a CIN surrogate to predict prognosis, chemotherapeutic and immune responses in CRC samples. Our results demonstrate the potential value of CIN as a therapeutic target in CRC treatment and the importance of BCL-XL in regulating survival of high-CIN CRC cells, therefore representing a valuable attempt to translate a common trait of heterogeneous tumor cells into an effective therapeutic target.