Human Colon Cancer Cells Research Articles

Antiproliferative in Vitro Evaluation of Terpenic Amines Synthesized via a Rhodium-catalyzed Hydroaminomethylation.

Terpene-derived alkaloids show a variety of biological activities, including antioxidant, anti-inflammatory, antimicrobial and cytotoxicity effects. In this work, homologated monoterpene amines have been prepared via a rhodium-catalyzed hydroaminomethylation of biomass-based alkenes, such as (R)-limonene, linalool, myrcene and camphene, in combination with secondary amines of aliphatic and aromatic nature, namely morpholine and N-methylaniline, leading to highly chemo- and regioselective processes. The as-prepared amines were obtained in 50-99 % overall yields, and in vitro tested on a human colon cancer cell line (HCT-116) to evaluate their cytotoxic potential. The lead compound of the series (3 a) showed cytotoxicity in the micromolar range (IC50 52.46 μM) via the induction of cell death by apoptosis, paving the way towards further structure-activity relationship studies.

MT1G Regulates c-MYC/P53 Signal to Inhibit Proliferation, Invasion and Migration and Promote Apoptosis in Colon Cancer Cells.

Colon cancer is a common and malignant cancer featuring high morbidity and poor prognosis. This study was performed to explore the regulatory role of MT1G in colon cancer as well as its unconcealed molecular mechanism. The expressions of MT1G, c-MYC, and p53 were assessed with the application of RT-qPCR and western blot. The impacts of MT1G overexpression on the proliferative ability of HCT116 and LoVo cells were measured by CCK-8 and BrdU incorporation assays. Additionally, transwell wound healing, and flow cytometry assays were employed to evaluate the invasive and migrative capacities as well as the apoptosis level of HCT116 and LoVo cells. Moreover, the activity of the P53 promoter region was assessed with the help of a luciferase reporter assay. It was found that the expressions of MT1G at both mRNA and protein levels were greatly decreased in human colon cancer cell lines, particularly in HCT116 and LoVo cell lines. After transfection, it was discovered that the MT1G overexpression suppressed the proliferation, migration and invasion but promoted the apoptosis of HCT116 and LoVo cells, which were then partially reversed after overexpressing c-MYC. Additionally, MT1G overexpression reduced c-MYC expression but enhanced the p53 expression, revealing that the MT1G overexpression could regulate c-MYC/P53 signal. Elsewhere, it was also shown that c-MYC overexpression suppressed the regulatory effects of MT1G on P53. To conclude, MT1G was verified to regulate c-MYC/P53 signal to repress the proliferation, migration and invasion but promote the apoptosis of colon cancer cells, which might offer a novel targeted-therapy for the improvement of colon cancer.

The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance

ABSTRACT Intratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land’s cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5∆ClbQ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.

Schisandrin B Suppresses Colon Cancer Growth by Inducing Cell Cycle Arrest and Apoptosis: Molecular Mechanism and Therapeutic Potential.

Colon cancer is among the most lethal and prevalent malignant tumors in the world, and the lack of effective therapies highlights the need for novel therapeutic approaches. Schisandrin B (Sch B), a lignan extracted from the fruit ofSchisandra chinensis, has been reported for its anticancer properties. However, to date, no studies have been done to characterize the exact molecular mechanisms underlying the antitumorigenic effects of Sch B in colon cancer. This study aimed to explore the antitumorigenic effects of Sch B in colon cancer and to understand the underlying therapeutic mechanism. A comprehensive analysis of the molecular mechanism underlying the antitumorigenic effects of Sch B on human colon cancer cells was performed using a combination of Raman spectroscopy, RNA-seq, computational docking, and molecular biological experiments. The in vivo efficacy was evaluated by a mouse xenograft model. Sch B reduced cell proliferation and triggered apoptosis in human colon cancer cell lines. Raman spectroscopy, computational, RNA-seq, and molecular and cellular studies revealed that Sch B activated unfolded protein responses by interacting with CHOP and upregulating CHOP, which thereby induced apoptosis. CHOP knockdown alleviated the Sch B-induced reduction in cell viability and apoptosis. Sch B reduced colon tumor growth in vivo. Our findings demonstrated that Sch B induced apoptosis and inhibited cell proliferation and tumor growth in vitro and in vivo. These results provided an essential background for clinical trials examining the effects of Sch B in patients with colon cancer.

Exploration of novel 6,8,9-trisubstituted purine analogues: synthesis, in vitro biological evaluation, and their effect on human cancer cells.

Cancer, a leading global cause of mortality, demands continuous advancements in therapeutic strategies. This study focuses on the design and synthesis of a novel series of purine derivatives, specifically 6-(substituted phenyl piperazine)-8-(4-phenoxyphenyl)-9-cyclopentyl purine derivatives (5-11). The motivation behind this endeavor lies in addressing acquired resistance mechanisms in cancer cells, a significant hurdle in current treatment modalities. The synthesis, starting from 4,6-dichloro-5-nitropyrimidine, involves a multi-step process, resulting in seven new purine derivatives. Biological evaluation against human liver, colon, and breast cancer cells (Huh7, HCT116, and MCF7, respectively) was performed using the SRB assay. Among the synthesized analogs, compounds 5 and 6, exhibited notable cytotoxic activity, surpassing clinically used positive controls 5-Fluorouracil and Fludarabine in terms of efficacy. This research underscores the potential of purine derivatives with a phenyl group at the C-8 position as a scaffold for developing compounds with improved anticancer properties. The findings offer insights for future exploration and development of novel agents in cancer pharmaceutical research.

Diterpenoids from Torreya grandis and their cytotoxic activities

Eight previously undescribed diterpenoids, along with eleven previously reported analogues, were obtained from the supercritical CO2 extracts of Torreya grandis aril. The structures of these compounds were elucidated based on HRESIMS, NMR, ECD, and single-crystal X-ray diffraction data. In the MTT assay, compound 18 exhibited significant inhibitory effects on two human colon cancer cell lines, HT-29 and HCT 116 cells, with IC50 values of 7.37 μM and 6.55 μM, respectively. It was found that compound 18 induced apoptosis and significantly inhibited the migration of HCT 116 colon cancer cells in a concentration-dependent manner.

A microelectrode electrochemical sensing platform based on heteroatoms doped carbon nanotubes arrays with peroxidase-like activity for in-situ detection in live cell

In this work, we developed a new strategy to fabricate a series of transition metallic nanoparticles (NPs) embedded on B, N co-doped carbon nanotubes (CNTs) arrays modified flexible carbon fiber electrodes (M@BNCNTs/CF, M = Co, Fe, Ni) via facile inkjet printing assisted with chemical vapor deposition using Ionic liquid as solvent of printing ink and heteroatom dopants. Furthermore, Pt NPs via impregnation-thermal reduction process was anchored on the surface of Co@BNCNTs/CF (Pt–Co@BNCNTs/CF), which holds enhanced peroxidase-like activity and could be directly used as freestanding electrode to detect H2O2, exhibiting a low detection limit of 0.19 μM with wide linear range (0.5 μM–9.4 mM), and high sensitivity (1679 μA cm−2 mM−1). The excellent sensing performance of Pt–Co@BNCNTs/CF is attributed to the Pt, Co NPs anchored on CNTs with great catalytic activity, and the doping B, N would cause graphitic carbon with more defects to improve its inherent reactivity toward H2O2. Besides, CNTs arrays with high surface area also enlarge the exposure of active sites. Moreover, the Pt–Co@NBCNTs/CF microelectrode has been successfully applied in monitoring H2O2 secreted from human colonic cancer cells and normal colonic epithelial cells, which could offer crucial data for distinguishing various cell types and identifying cancer cells from normal cells. This work opens a new horizon to fabricate flexible miniaturized sensing device for extracellular analysis and offers an extended strategy to fabricate other metallic NPs embedded in heteroatoms doped CNTs functionalized flexible fiber electrode, by choosing diverse metal ions and ILs as inkjet printing precursors.

Potential of Melittin to induce apoptosis and overcome multidrug resistance in human colon cancer cell line

In this study, the anticancer effect of Melittin was demonstrated through its antiproliferative and proapoptotic effects on HT-29 cells, as well as its ability to reverse multidrug resistance. Melittin directly affects the death receptor-dependent apoptotic pathway via increase of the Fas receptor protein expression, Caspase 8 gene expression and activity of Caspase 8. Results of decreased Caspase 9 gene and protein expression, and multi-fold increased expression of Bcl-2 gene suggest that mitochondria and the inner apoptotic pathway are not involved in the execution of Melittin induced apoptosis, as well as redox regulation of apoptosis based on decreased concentration of superoxide anion radicals and no effect glutathione levels. Specially significance of this work are results on ability of Melittin to modulate the metabolism and export system in cancer cells. Based on the increased expression of all the investigated genes related to the biotransformation process, it can be assumed that CYP1A1, CYP1B1, GSTP1 and MRP2 are involved in metabolism of Melittin in HT-29 cells. P-glycoprotein is associated with the occurrence of resistance in anticancer therapy, so its reduced gene and protein expression by Melittin represents significant result in terms of possible therapeutic application and examination.

Synthesis, characterization, molecular modeling studies, and biological evaluation of metal piroxicam complexes (M = Ni(II), Pt(IV), Pd(II), Ag(I)) as antibacterial and anticancer agents.

Four piroxicam metal complexes; NiL2 , PtL2 , PdL2 , and AgL were synthesized and characterized by different techniques with enhanced antibacterial and anticancer activity. Regarding in vitro antimicrobial activity, complex NiL2 displayed potent antibacterial effect against Escherichia coli and Pseudomonas aeruginosa that was 1.9-folds higher than piroxicam (minimum inhibitory concentration [MIC] = 31.85, 65.32 µM), respectively. In case of G+ve bacteria, complex PtL2 had potent activity on Staphylococcus aureus which was 2.1-folds higher than piroxicam (MIC = 43.12 µM), while activity of complex AgL against Enterococcus faecalis was threefolds higher than piroxicam (MIC = 74.57 µM. Complexes PtL2 and PdL2 exhibited higher inhibition of DNA gyrase than piroxicam (IC50 = 6.21 µM) in the range of 1.9-1.7-folds. The in vitro antiproliferative activity depicted that all investigated complexes showed better cytotoxic effect than piroxicam, specifically Pt and Pd complexes which had lower IC50 values than piroxicam on human liver cancer cell line HepG2 by 1.8 and 1.7-folds, respectively. While Pd and Ag complexes showed 2 and 1.6-folds better effect on human colon cancer cell line HT-29 compared with piroxicam. Molecular modeling studies including docking on Stranded DNA Duplex (1juu) and DNA gyrase enzyme (1kzn) that gave good insight about interaction of complexes with target molecules, calculation of electrostatic potential map and global reactivity descriptors were performed.

Antibacterial, antibiofilm, and anticancer activity of silver-nanoparticles synthesized from the cell-filtrate of Streptomyces enissocaesilis

Silver nanoparticles (Ag-NPs) have a unique mode of action as antibacterial agents in addition to their anticancer and antioxidant properties. In this study, microbial nanotechnology is employed to synthesize Ag-NPs using the cell filtrate of Streptomyces enissocaesilis BS1. The synthesized Ag-NPs are confirmed by ultraviolet-visible (UV-Vis), Fourier transform infrared (FT-IR), X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Also, the effects of different factors on Ag-NPs synthesis were evaluated to set the optimum synthesis conditions. Also, the antibacterial, antibiofilm, and anticancer activity of Ag-NPs was assessed. The X-ray diffraction (XRD) analysis confirmed the crystalline nature of the sample and validated that the crystal structure under consideration is a face-centered cubic (FCC) pattern. The TEM examination displayed the spherical particles of the Ag-NPs and their average size, which is 32.2 nm. Fourier transform infrared spectroscopy (FTIR) revealed significant changes in functionality after silver nanoparticle dispersion, which could be attributed to the potency of the cell filtrate of Streptomyces enissocaesilis BS1 to act as both a reducing agent and a capping agent. The bioactivity tests showed that our synthesized Ag-NPs exhibited remarkable antibacterial activity against different pathogenic strains. Also, when the preformed biofilms of Pseudomonas aeruginosa ATCC 9027, Salmonella typhi ATCC 12023, Escherichia coli ATCC 8739, and Staphylococcus aureus ATCC 6598 were exposed to Ag NPs 50 mg/ml for 24 hours, the biofilm biomass was reduced by 10.7, 34.6, 34.75, and 39.08%, respectively. Furthermore, the Ag-NPs showed in vitro cancer-specific sensitivity against human breast cancer MCF-7 cell lines and colon cancer cell line Caco-2, and the IC50 was 0.160 mg/mL and 0.156 mg/mL, respectively. The results of this study prove the ease and efficiency of the synthesis of Ag-NPs using actinomycetes and demonstrate the significant potential of these Ag-NPs as anticancer and antibacterial agents.

Everolimus exerts anticancer effects through inhibiting the interaction of matrix metalloproteinase-7 with syndecan-2 in colon cancer cells.

Previous work showed that matrix metalloproteinase-7 (MMP-7) regulates colon cancer activities through an interaction with syndecan-2 (SDC-2) and SDC-2-derived peptide that disrupts this interaction and exhibits anticancer activity in colon cancer. Here, to identify potential anticancer agents, a library of 1,379 Food and Drug Administration (FDA)-approved drugs that interact with the MMP-7 prodomain were virtually screened by protein-ligand docking score analysis using the GalaxyDock3 program. Among five candidates selected based on their structures and total energy values for interacting with the MMP-7 prodomain, the known mechanistic target of rapamycin kinase (mTOR) inhibitor, everolimus, showed the highest binding affinity and the strongest ability to disrupt the interaction of the MMP-7 prodomain with the SDC-2 extracellular domain in vitro. Everolimus treatment of the HCT116 human colon cancer cell line did not affect the mRNA expression levels of MMP-7 and SDC-2 but reduced the adhesion of cells to MMP-7 prodomain-coated plates and the cell-surface localization of MMP-7. Thus, everolimus appears to inhibit the interaction between MMP-7 and SDC-2. Everolimus treatment of HCT116 cells also reduced their gelatin-degradation activity and anticancer activities, including colony formation. Interestingly, cells treated with sirolimus, another mTOR inhibitor, triggered less gelatin-degradation activity, suggesting that this inhibitory effect of everolimus was not due to inhibition of the mTOR pathway. Consistently, everolimus inhibited the colony-forming ability of mTOR-resistant HT29 cells. Together, these data suggest that, in addition to inhibiting mTOR signaling, everolimus exerts anticancer activity by interfering with the interaction of MMP-7 and SDC-2, and could be a useful therapeutic anticancer drug for colon cancer.NEW & NOTEWORTHY The utility of cancer therapeutics targeting the proteolytic activities of MMPs is limited because MMPs are widely distributed throughout the body and involved in many different aspects of cell functions. This work specifically targets the activation of MMP-7 through its interaction with syndecan-2. Notably, everolimus, a known mTOR inhibitor, blocked this interaction, demonstrating a novel role for everolimus in inhibiting mTOR signaling and impairing the interaction of MMP-7 with syndecan-2 in colon cancer.

Anti-parkinsonian, anti-inflammatory, anti-microbial, analgesic, anti-hyperglycemic and anticancer activities of poly-fused ring pyrimidine derivatives

Purpose: To investigate the anti-inflammatory, anti-cancer, anti-parkinsonian, anti-microbial, analgesic, and anti-hyperglycemic properties of a variety of poly-fused pyrimidine derivatives.
 Methods: A novel series of fused pyrimidine derivatives 1-6 were synthesized by reacting amino pyrazole derivatives with active methylene derivatives to give the corresponding compounds 1-6. Anti-parkinsonian activity was investigated with benzotropene as a reference drug, anti-inflammatory effect in mice was evaluated using carrageenan in paw edema with indomethacin as reference drug, anti-microbial activity was assessed using nutritional agar with ciprofloxacin and ketoconazole as reference drugs, analgesic activity was evaluated using valdecoxib as reference drug, anti-hyperglycemic activity was investigated using alloxan and sucrose models (SLM) with pioglitazone as reference drug and anticancer activity was investigated using the MTT micro-cultured tetrazolium assay method with doxorubicin as reference drug.
 Results: Pyrimidine derivatives 1-6 possess significant active anti-parkinsonian, anti-inflammatory, anti-microbial, analgesic, anti-hyperglycemic and anticancer activities in comparison to the reference drugs used for each model. Compared to Benzotropene®, compounds 1 and 3 showed a significantly stronger anti-parkinsonian activity (p < 0.03). Compound 3 showed a significantly stronger anti-inflammatory effect than Indomethacin® (p < 0.05). Compounds 5 and 6 exhibited significant anti- microbial activity compared to ciprofloxacin® (p < 0.05). Compounds 4 and 6 exhibited significantly improved analgesic activity as compared to Valdecoxib® (p < 0.01). Compounds 1 and 3 exhibited significantly higher anti-hyperglycemic effects in SLM model when compared to pioglitazone® (p < 0.02). Compound 5 demonstrated the highest activity against human colon cancer cell line (HT-29) and human prostate cancer cell line (DU145), and also, significantly improved level of efficacy against human lung cancer cell line (A549) compared to Doxorubicin® (p < 0.02). 
 Conclusion: Using the six pyrimidine derivatives 1 - 6 as a lead molecule, a novel class of clinically beneficial anti-cancer, anti-inflammatory, anti-microbial, analgesic, and anti-hyperglycemic drugs may be produced.

The Expression and Role of Aquaporin 4 in Colon Cancer.

Aquaporins (AQPs) were initially discovered as water channel proteins that facilitate transcellular water movements. Recent studies have shown that AQPs are expressed and play an oncogenic role in various cancers. However, the expression and role of Aquaporin 4 (AQP4) in colon cancer have not been investigated. This study aimed to examine the clinical and pathophysiologic significance of AQP4 in colon cancer. Immunohistochemistry (IHC) of AQP4 for 145 primary tumor samples obtained from patients with stage II or III colon cancer was performed, and the relationship between AQP4 expression and patients' prognoses was analyzed. Knockdown experiments with AQP4 small interfering RNA using human colon cancer cells were conducted to analyze the effects on cell invasiveness. IHC revealed that AQP4 was scarcely expressed in the noncancerous colonic mucosa. Of the 145 patients who enrolled in this study, 109 (75.2%) and 36 (24.8%) patients were classified as negative and positive for AQP4 expression, respectively. A high level of AQP4 expression is significantly associated with deeper tumors with lymph node metastasis and venous invasion. A 5-year progression-free survival rate of AQP4-positive patients was significantly worse than that of AQP-4 negative patients (70.7% vs. 87.0%, p=0.049). Furthermore, AQP4 knockdown significantly inhibited cell migration and invasion in HCT116 cells. AQP4 may be a novel biomarker and therapeutic target for colon cancer.

Effect of Pioglitazone and Cetuximab on Colon Cancer Stem-like Cell (CCSLCs) Properties.

One of the main reasons for cancer resistance to chemotherapy is the presence of cancer stem cells (CSCs) in cancer tissues. It is also believed that CSCs are the unique originators of all tumor cells. On the other hand, the Epithelial-Mesenchymal Transition pathway (EMT) can act as the main agent of metastasis. Therefore, it is possible that targeting CSCs as well as the EMT pathway could help in cancer therapy. Considering that CSCs constitute only a small percentage of the total tumor mass, enrichment before study is necessary. In our previous study, CSCs were enriched in the human colon cancer cell line HT29 by induction of EMT. These CSC-enriched HT29 cells with mesenchymal morphology were named "HT29-shE". In the present study, these cells were used to investigate the effect of pioglitazone (Pio) and Cetuximab (Cet) in order to find CSC and EMT targeting agents. The viability and IC50 rate of cells treated with different concentrations of Pio and Cet were evaluated using the MTT test. EMT and CSC markers and cell morphology were assessed in Pio and Cet treated and untreated HT29-shE cells using flow cytometry, realtime PCR, immunocytochemistry, and microscopic monitoring. The findings showed that Pio and Cet at concentrations of 250 μM and 40 μg/ml, respectively, decrease cell viability by 50%. Also, they were able to reduce the expression of CSC markers (CD133 and CD44) in the CSC enriched HT29 cell line. Furthermore, Pio and Cet could efficiently reduce the expression of vimentin as a mesenchymal marker and significantly upregulate the expression of E-cadherin as an epidermal marker of EMT and its reverse mesenchymal-- to-epithelial transition (MET). In addition, the mesenchymal morphology of HT29-shE changed into epithelial morphology after Cet treatment. Pio and Cet could inhibit EMT and reduce CSC markers in the EMT induced/CSC enriched cell line. We expect that focus on finding EMT/CSC-targeting agents like these drugs can be helpful for cancer treatment.

P024 Synergistic effect of phytochemicals combination including ginsenosides and curcumin on recovery from radiation-induced toxicity

Abstract Background Radiotherapy is commonly used to treat solid cancers located in the pelvis. A considerable number of patients experience proctitis of varying severity, even for a considerable period after radiotherapy. These side effects are often long-lasting or progressively worsen despite multiple therapeutic efforts and are a primary cause of an unexpectedly low quality of life, even after successful cancer treatment. Therefore, this in vitro study, as an initial trial, evaluated the single and combined efficacy of ginsenoside, curcumin, butyric acid, and sucralfate compounds in treating radiation-induced proctitis. Methods Cell viability and migration assay, endothelial cell tube formation assay were performed using human colon cancer cell lines, dermal fibroblasts, keratinocytes, and human umbilical vein endothelial cells, which were exposed to radiation. In addition, Inflammatory cytokine assay for CXCL10, CCL2, CCL8, IFN-γ, IL-4, IL-12, and IL-21 is performed using human monocytes treated with LPS (lipopolysaccharide). In all assay, the single and combined efficacy of ginsenoside, curcumin, butyric acid, and sucralfate were analyzed. Results While the candidate compounds did not affect the proliferation and migration of cancer cells, they promoted the recovery of cell activity, including motility. They exhibited anti-inflammatory effects on human dermal fibroblasts or human umbilical vein endothelial cells within in vitro disease models. When each compound was tested, curcumin and ginsenoside were the most effective in cell recovery and promoted the migration of human dermal fibroblasts and cell restoration of human umbilical vein endothelial cells. The combination of ginsenoside and curcumin resulted in cell migration recovery of approximately 54%. In addition, there was a significant improvement in the length of the endothelial tube, with an increase of approximately 25%, suggesting that the ginsenoside-curcumin-containing combination was the most effective against radiation-induced damage. Furthermore, it was shown that the combination could alleviate radiation-induced inflammation by reducing the concentrations of IFN-γ and IL-12, associated with activated macrophages among LPS-induced inflammatory cytokines, by approximately 20% and 45%, respectively. Conclusion Our study provides valuable insights into using curcumin and ginsenoside as potential compounds for the effective treatment of radiation-induced injuries and highlights the promising therapeutic benefits of combining these two compounds.

Innovative microwave-assisted biosynthesis of copper oxide nanoparticles loaded with platinum(ii) based complex for halting colon cancer: cellular, molecular, and computational investigations.

In the current study, we biosynthesized copper oxide NPs (CuO NPs) utilizing the essential oils extracted from Boswellia carterii oleogum resin, which served as a bioreductant and capping agent with the help of microwave energy. Afterwards, the platinum(ii) based anticancer drug, carboplatin (Cr), was loaded onto the CuO NPs, exploiting the electrostatic interactions forming Cr@CuO NPs. The produced biogenic NPs were then characterized using zeta potential (ZP), high-resolution transmission electron microscopy (HRTEM), X-ray diffraction spectroscopy (XRD), and Fourier transform infrared spectroscopy (FTIR) techniques. In addition, the entrapment efficiency and release profile of the loaded Cr were evaluated. Thereafter, SRB assay was performed, where Cr@CuO NPs demonstrated the highest cytotoxic activity against human colon cancer cells (HCT-116) with an IC50 of 5.17 μg mL-1, which was about 1.6 and 2.2 folds more than that of Cr and CuO NPs. Moreover, the greenly synthesized nanoparticles (Cr@CuO NPs) displayed a satisfactory selectivity index (SI = 6.82), which was far better than the free Cr treatment (SI = 2.23). Regarding the apoptosis assay, the advent of Cr@CuO NPs resulted in an immense increase in the cellular population percentage of HCT-116 cells undergoing both early (16.02%) and late apoptosis (35.66%), significantly surpassing free Cr and CuO NPs. A study of HCT-116 cell cycle kinetics revealed the powerful ability of Cr@CuO NPs to trap cells in the Sub-G1 and G2 phases and impede the G2/M transition. RT-qPCR was utilized for molecular investigations of the pro-apoptotic (Bax and p53) and antiapoptotic genes (Bcl-2). The novel Cr@CuO NPs treatment rose above single Cr or CuO NPs therapy in stimulating the p53-Bax mediated mitochondrial apoptosis. The cellular and molecular biology investigations presented substantial proof of the potentiated anticancer activity of Cr@CuO NPs and the extra benefits that could be obtained from their use.

Synthesis, Characterization, Investigation of Anticancer Activity and Molecular Docking Studies of N2O2 Type Schiff Base Ligand and Metal Complexes

AbstractSchiff base ligands and their metal complexes play a great important role in pharmaceutical sciences because of their wide and significant activities. They are versatile pharmacophores for the design and discovery of many drugs. In this study, a Schiff base ligand and its complexes were synthesized. Some spectroscopic techniques such as FT‐IR, 1H‐NMR, 13C‐NMR, XRD, SEM, and UV‐Vis were used for structural characterization. Antiproliferative activities of the synthesized ligand and complexes were investigated on the human breast (MCF‐7) and colon (HT‐29) cancer cell lines by XTT [2,3‐Bis(2‐methoxy‐4‐nitro‐5‐sulfophenyl)‐2H‐tetrazolium] method. The obtained data showed that the ligand and complexes exhibited dose‐dependent and cell‐selective in vitro antiproliferative activity on the tested cell line. In addition, it was determined that complexes showed statistically higher cytotoxic activity compared to the ligand. The binding parameter values and the important amino acids in the binding site were determined between the possible lead compounds synthesized by molecular docking from in silico approaches and the target. A molecular docking study of the cobalt complex was performed against Bcl‐2 (PDB ID:4IEH) and DNA recognition (PDB ID:423D) targets. In conclusion, these data show that the synthesized Schiff base ligand and metal complexes have the potential to be evaluated as a chemotherapeutic agent.

The non-vesicle cell-free DNA (cfDNA) induces cell transformation associated with horizontal DNA transfer.

Cell-free DNA (cfDNA) is a source for liquid biopsy used for cancer diagnosis, therapy selection, and disease monitoring due to its non-invasive nature and ease of extraction. However, cfDNA also participates in cancer development and progression by horizontal transfer. In humans, cfDNA circulates complexed with extracellular vesicles (EV) and macromolecular complexes such as nucleosomes, lipids, and serum proteins. The present study aimed to demonstrate whether cfDNA not associated with EV induces cell transformation and tumorigenesis. Supernatant of the SW480 human colon cancer cell line was processed by ultracentrifugation to obtain a soluble fraction (SF) and a fraction associated with EV (EVF). Primary murine embryonic fibroblast cells (NIH3T3) underwent passive transfection with these fractions, and cell proliferation, cell cycle, apoptosis, cell transformation, and tumorigenic assays were performed. Next, cfDNA was analyzed by electronic microscopy, and horizontal transfer was assessed by human mutantKRASin recipient cells via PCR and recipient cell internalization via fluorescence microscopy. The results showed that the SF but not the EVF of cfDNA induced proliferative and antiapoptotic effects, cell transformation, and tumorigenesis in nude mice, which were reduced by digestion with DNAse I and proteinase K. These effects were associated with horizontal DNA transfer and cfDNA internalization into recipient cells. The results suggest pro-tumorigenic effects of cfDNA in the SF that can be offset by enzyme treatment. Further exploration of the horizontal tumor progression phenomenon mediated by cfDNA is needed to determine whether its manipulation may play a role in cancer therapy.

Synthesis of 1-(4-chlorobenzoyl)-4-(dimethylamino) pyridin-1-ium chloride and determination of cytotoxicity and apoptosis in human colon cancer cells

BackgroundIn this experiment, we synthesized a new compound, 1-(4-chlorobenzoyl)-4-(dimethylamino) pyridin-1-ium chloride (SM-9), and examined its toxicity and anticancer activity in human colon cancer (HCT-116) cells. MethodsWe uncovered the underlying mechanisms of cell toxicity and apoptosis due to SM-9 compound exposure in HCT-116 cells by using the MTT assay and protein profiling array and measuring gene expression levels using reverse transcription-polymerase chain reaction. ResultsOur data show that the SM-9 compound activated the caspase-3, caspase-8, p21, p27, and p53 proteins involved in the apoptosis of HCT-116 cells, thereby inducing cytotoxicity, the formation of reactive oxygen species, and apoptosis. The results of this study show that the SM-9 compound has advantageous qualities and must be taken as an anticancer medication. We conclude that the SM-9 compound exerted an anticancer effect by inducing the apoptotic pathways in human colon cancer (HCT-116) cells.

A Facile Ugi/Ullmann Cascade Reaction to Access Fused Indazolo-Quinoxaline Derivatives with Potent Anticancer Activity.

A facile methodology for the construction of a complex heterocycle indazolo-fused quinoxalinone has been developed via an Ugi four-component reaction (U-4CR) followed by an intramolecular Ullmann reaction. The expeditious process features an operationally simple approach, time efficiency, and a broad substrate scope. Biological activity was evaluated and demonstrated that compound 6e inhibits human colon cancer cell HCT116 proliferation with an IC50 of 2.1 μM, suggesting potential applications for developing a drug lead in medicinal chemistry.