Human Colon Tumor Cell Research Articles

Evaluating the pharmacological activities of Aloe perryi-Silver nanoparticles induced apoptosis against colon cancer cells (HCT-116).

Aloe perryi has been studied and possesses several activities, including antibacterial, antiparasitic, and anticancer properties. In this study, A. perryi was used as a reducing agent of silver ions into silver nanoparticles. Aloe perryi-silver nanoparticles (APS-NPs) were characterized and evaluated using characterization techniques. However, the antioxidative, antibacterial, and anticancer assays were studied to evaluate the pharmacological activities of APS-NPs. APS-NPs were developed and changed to dark brown and the maximum absorption was 442 nm. SEM (5-583 nm), TEM (4-110 nm), XRD (21.84 nm), and zeta potential analysis (63.39 nm) revealed that the APS-NPs were nano-sized, and the APS-NPs had a cubic crystalline structure, according to the XRD results. FTIR analysis suggested that functional groups of A. perryi metabolites were involved in forming APS-NPs. The zeta potential indicated that the APS-NPs were negatively charged (-32 mV), suggesting good stability. APS-NPs showed significant antioxidative stress activity by reducing DPPH-free radicles in a dose-dependent manner. APS-NPs-induced antibacterial effect against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and Acinetobacter baumannii (A. baumannii). APS-NPs reduced the cell viability and cell migration of the human colon tumor cell line (HCT 116) compared with controls, indicating that APS-NPs could play a role in reducing metastasis and inducing cell apoptosis against colon cancer. In conclusion, the nanoparticle synthesis from A. perryi extract demonstrated excellent antioxidant, antibacterial, and anticancer activities, thus suggesting that our APS-NPs have the potential to be used as antioxidative and antibacterial in food and pharmaceutical industries.

Cytotoxic prenylated phenols of false indigo-bush (Amorpha fruticosa L.)

This study employed the MTT assay to assess the cytotoxicity of one flavan and two stilbene derivatives isolated from the false indigo-bush (Amorpha fruticosa L.) fruits: 5,7-dihydroxy-8-geranylflavanone (1), 2-carboxy-3,5-dihydroxy-4-geranylbibenzyl (2), and 2-carboxy-3-hydroxy-4-prenyl-5-methoxybibenzyl (3). The examined compounds reduced the survival of human cervical and colon tumour cells (HeLa, HT-29, HCT-116, and LS174) with IC50 values ranging from 10.55 to 147.09 μg/mL, except for 1, which did not affect LS174 cells within the tested concentrations. The highest activity was observed for 1 against HeLa cells, and 1 also exhibited the weakest effect against normal foetal lung fibroblasts (IC50 = 166.11 μg/mL), demonstrating good potency and selectivity. Stilbenes 2 and 3 proved efficacious, but lacked selectivity compared to 1. Our findings revealed the cytotoxicity of false indigo-bush constituents, justifying further mechanistic and in vivo investigations, particularly on 5,7-dihydroxy-8-geranylflavanone, which displayed considerable in vitro anticancer capacity and a potentially favourable safety profile.

Molecular Targets of the 5-Amido-Carboxamide Bumped Kinase Inhibitor BKI-1748 in Cryptosporidium parvum and HCT-8 Host Cells.

Cryptosporidium parvum is an apicomplexan parasite causing persistent diarrhea in humans and animals. Issuing from target-based drug development, calcium-dependent protein kinase 1 inhibitors, collectively named bumped kinase inhibitors (BKIs), with excellent efficacies in vitro and in vivo have been generated. Some BKIs including BKI-1748 share a core structure with similarities to the first-generation antiprotozoal drug quinine, which is known to exert notorious side effects. Unlike quinine, BKI-1748 rapidly interfered with C. parvum proliferation in the human colon tumor (HCT) cell line HCT-8 cells and caused dramatic effects on the parasite ultrastructure. To identify putative BKI targets in C. parvum and in host cells, we performed differential affinity chromatography with cell-free extracts from non-infected and infected HCT-8 cells using BKI-1748 and quinine epoxy-activated sepharose columns followed by mass spectrometry. C. parvum proteins of interest were identified in eluates from columns coupled to BKI-1748, or in eluates from both BKI-1748 and quinine columns. However, no C. parvum proteins could be identified binding exclusively to BKI-1748. In contrast, 25 BKI-1748-specific binding proteins originating from HCT-8 cells were detected. Moreover, 29 C. parvum and 224 host cell proteins were identified in both BKI-1748 as well as in quinine eluates. In both C. parvum and host cells, the largest subset of binding proteins was involved in RNA binding and modification, with a focus on ribosomal proteins and proteins involved in RNA splicing. These findings extend previous results, showing that BKI-1748 interacts with putative targets involved in common, essential pathways such as translation and RNA processing.

Discovery of a synthetic taiwaniaquinoid with potent in vitro and in vivo antitumor activity against breast cancer cells

Taiwaniaquinoids are a unique family of diterpenoids predominantly isolated from Taiwania cryptomerioides Hayata. Previously, we evaluated the antiproliferative effect of several synthetic taiwaniaquinoids against human lung (A-549), colon (T-84), and breast (MCF-7) tumor cell lines. Herein, we report the in vitro and in vivo antitumor activity of the most potent compounds. Their cytotoxic activity against healthy peripheral blood mononuclear cells (PBMCs) has also been examined. We underscore the limited toxicity of compound C36 in PBMCs and demonstrate that it exerts its antitumor effect in MCF-7 cells (IC50 = 1.8 µM) by triggering an increase in reactive oxygen species, increasing the cell population in the sub-G1 phase of the cell cycle (90 %), and ultimately activating apoptotic (49.6 %) rather than autophagic processes. Western blot results suggested that the underlying mechanism of the C36 apoptotic effects was linked to caspase 9 activation and a rise in the Bax/Bcl-2 ratio. In vivo analyses showed normal behavior and hematological parameters in C57BL/6 mice post C36 treatment. Moreover, no significant impact was observed on the biochemical parameters of these animals, indicating that C36 did not induce liver toxicity. Furthermore, C36 demonstrated a significant reduction in tumor growth in immune-competent C57BL/6 mice implanted with E0771 mouse mammary tumor cells, effectively improving survival rates. These findings position taiwaniaquinoids, particularly compound C36, as promising therapeutic candidates for human breast cancer.

Preparation and Properties of Natural Polysaccharide-Based Drug Delivery Nanoparticles.

In recent years, natural polysaccharides have been widely used in the preparation of drug delivery systems. In this paper, novel polysaccharide-based nanoparticles were prepared by layer-by-layer assembly technology using silica as a template. The layers of nanoparticles were constructed based on the electrostatic interaction between a new pectin named NPGP and chitosan (CS). The targeting ability of nanoparticles was formed by grafting the RGD peptide, a tri-peptide motif containing arginine, glycine, and aspartic acid with high affinity to integrin receptors. The layer-by-layer assembly nanoparticles (RGD-(NPGP/CS)3NPGP) exhibited a high encapsulation efficiency (83.23 ± 6.12%), loading capacity (76.51 ± 1.24%), and pH-sensitive release property for doxorubicin. The RGD-(NPGP/CS)3NPGP nanoparticles showed better targeting to HCT-116 cells, the integrin αvβ3 high expression human colonic epithelial tumor cell line with higher uptake efficiency than MCF7 cells, the human breast carcinoma cell line with normal integrin expression. In vitro antitumor activity tests showed that the doxorubicin-loaded nanoparticles could effectively inhibit the proliferation of the HCT-116 cells. In conclusion, RGD-(NPGP/CS)3NPGP nanoparticles have potential as novel anticancer drug carriers because of their good targeting and drug-carrying activity.

Nucleotide Supplements Alter Proliferation and Differentiation of Cultured Human (Caco-2) and Rat (IEC-6) Intestinal Epithelial Cells

The effect of exogenous nucleotides on the proliferation and differentiation of enterocytes was comparatively studied using a human colon tumor cell line (Caco-2) and a normal rat small intestinal crypt cell line (IEC-6). Caco-2 cells exhibited more active endogenous nucleic acid metabolism than did IEC-6 cells, as evidenced by greater cellular pools of nucleotides and their metabolites. To determine the supplemental nutritional effect of nucleotides, a mixture containing equal amounts (10 mg/L) of AMP, CMP, IMP, GMP and UMP was added to the culture medium. The results showed that a nucleotide supplement under normal culture conditions did not affect proliferation and differentiation of Caco-2 cells. In contrast, nucleotide supplements under normal culture conditions promoted proliferation of IEC-6 cells. The addition of nucleotides to the culture medium also enhanced differentiation of IEC-6 cells when grown on an extracellular matrix (Matrigel). Furthermore, when glutamine levels were less than optimal (nutritional stress conditions), nucleotide supplements enhanced growth and maturation of both cell lines. We conclude that the de novo biosynthesis of nucleotides is sufficient to support proliferation of tumor Caco-2 cells but not of the normal crypt IEC-6 cells. Thus, nucleotide supplements may enhance normal enterocyte growth and maturation as well as spare the need for exogenous glutamine in cell maintenance and development.

Ethylcoprostanol modulates colorectal cancer cell proliferation and mitigates cytotoxicity of cholesterol metabolites in non-tumor colon cells.

Sterols can be metabolized by gut microbiota. The cholesterol metabolites have been proposed as promoters of colorectal cancer (CRC), while the effect of plant sterol metabolites is unknown. This study aimed to evaluate the cytotoxicity of metabolites from cholesterol (coprostanol, cholestanol, coprostanone and cholestenone) and β-sitosterol (ethylcoprostanol) on human colon tumor (Caco-2) and non-tumor (CCD-18Co) cells at physiological concentrations (9-300 μM) and exposure time (24 h). Ethylcoprostanol reduced the tumor cell proliferation (MTT), showing in flow cytometry assays induction of apoptosis via production of reactive oxygen species (ROS) and ceramide. Transcriptomic analysis (qPCR) showed activation of the intrinsic apoptosis pathway (BAX/BCL2 ratio and CASP9 increased), accompanied by downregulation of the p21 gene. Cholesterol metabolites, mainly the most hydrophobic, induced apoptosis and G0/G1 phase arrest in non-tumor cells through overproduction of ROS. Both the intrinsic and extrinsic (CASP8 increased) apoptosis pathways occurred. In turn, a reduction in the expression of the cyclin E1 gene confirmed the cell cycle arrest. In addition, ethylcoprostanol protected non-tumor cells from the most cytotoxic cholesterol metabolite (cholestenone). In conclusion, ethylcoprostanol is a promising candidate as a therapeutic adjuvant in CRC, while cholesterol metabolites could act as CRC promoters through their cytotoxicity.

Photoswitchable semiconducting polymer dots with photosensitizer molecule and photochromic molecule loading for photodynamic cancer therapy

Photodynamic therapy (PDT) is a new and rapidly developing treatment modality for clinical cancer therapy. Semiconductor polymer dots (Pdots) doped with photosensitizers have been successfully applied to PDT, and have made progress in the field of tumor therapy. However, the problems of severe photosensitivity and limited tissue penetration depth are needed to be solved during the implementation process of PDT. Here we developed the Pdots doped with photosensitizer molecule Chlorin e6 (Ce6) and photochromic molecule 1,2-bis(2,4-dimethyl-5-phenyl-3-thiophene)-3,3,4,5-hexafluoro-1-cyclopentene (BTE) to construct a photoswitchable nanoplatform for PDT. The Ce6-BTE-doped Pdots were in the green region, and the tissue penetration depth was increased compared with most Pdots in the blue region. The reversible conversion of BTE under different light irradiation was utilized to regulate the photodynamic effect and solve the problem of photosensitivity. The prepared Ce6-BTE-doped Pdots had small size, excellent optical property, efficient ROS generation and good photoswitchable ability. The cellular uptake, cytotoxicity, and photodynamic effect of the Pdots were detected in human colon tumor cells. The experiments in vitro indicated that Ce6-BTE-doped Pdots could exert excellent photodynamic effect in ON state and reduce photosensitivity in OFF state. These results demonstrated that this nanoplatform holds the potential to be used in clinical PDT.

Theoretical investigation and antineoplastic potential of Zn (II) and Pd (II) complexes of 6-methylpyridine-2-carbaldehyde-N (4)-ethylthiosemicarbazone

Density Functional Theoretical (DFT) and molecular docking studies have been used to elucidate the antineoplastic potential of the ligand 6-Methylpyridine-2-carbaldehyde-N (4)-ethylthiosemicarbazone (MET) and its platinum(II) and zinc(II) complexes. The frontier molecular orbital and the global quantum reactivity parameters were used to study the reactivity and stability of the modeled complexes. The energy gap showed that the complexes have their reactivity in the order Pd[MET] < [MET] < Zn[MET] suggesting a higher reactivity of the Pd complex compared to its Zn(II) congener. NBO indicated Pd(MET)Cl complex to have the highest E(2) energies and exhibiting highest interaction arising from strong coordination of the thiolato sulfur and chloride atoms around the Pd2+ as seen in the σ*S21 -Pd13→ σ*Pd31 – Cl32 transition. QTAIM revealed that highest density of electrons follows the order [Pd(MET)Cl] >[Zn(MET)Cl] > [MET], while computational drug design protocols carried out provided the order of binding affinity as Pd(MET)Cl > Zn(MET)Cl and MET which again presents Pd complex as having greater antineoplastic activity. Our DFT findings are in excellent agreement with previous experimental reports thereby affirming the potential of these complexes as possible candidates for antineoplastic chemotherapeutic treatment against the human colon tumor cell lines (HCT 116) .

Correlating Rheological Properties of a Gellan Gum-Based Bioink: A Study of the Impact of Cell Density.

Here, for the production of a bioink-based gellan gum, an amino derivative of this polysaccharide was mixed with a mono-functionalized aldehyde polyethyleneglycol in order to improve viscoelastic macroscopic properties and the potential processability by means of bioprinting techniques as confirmed by the printing tests. The dynamic Schiff base linkage between amino and aldehyde groups temporally modulates the rheological properties and allows a reduction of the applied pressure during extrusion followed by the recovery of gellan gum strength. Rheological properties, often related to printing resolution, were extensively investigated confirming pseudoplastic behavior and thermotropic and ionotropic responses. The success of bioprinting is related to different parameters. Among them, cell density must be carefully selected, and in order to quantify their role on printability, murine preostoblastic cells (MC3T3-E1) and human colon tumor cells (HCT-116) were chosen as cell line models. Here, we investigated the effect of their density on the bioink’s rheological properties, showing a more significant difference between cell densities for MC3T3-E1 compared to HCT-116. The results suggest the necessity of not neglecting this aspect and carrying out preliminary studies to choose the best cell densities to have the maximum viability and consequently to set the printing parameters.

Alkaloid Profiling, Anti-Enzymatic and Antiproliferative Activity of the Endemic Chilean Amaryllidaceae Phycella cyrtanthoides

This research aims to identify the alkaloid profile and to evaluate the enzyme inhibitory potential and antiproliferative effects of the Amaryllidaceae plant Phycella cyrtanthoides. The alkaloid extracts from bulbs and leaves were analyzed using ultrahigh performance liquid chromatography orbitrap mass spectrometry (UHPLC-Orbitrap-MS) analysis. A total of 70 alkaloids were detected in the P. cyrtanthoides’ extracts. The enzyme inhibition potential against cholinesterases (AChE: acetylcholinesterase, and BChE butyrylcholinesterase) and tyrosinase were studied. Bulbs displayed the best IC50 values against AChE (4.29 ± 0.03 µg/mL) and BChE (18.32 ± 0.03 µg/mL). These results were consistent with docking experiments with selected major compounds in the active sites of enzymes, while no activity was observed against tyrosinase enzyme. Antiproliferative effects were investigated against human cervical (HeLa), lung (A549, SW1573), colon (WiDr), and breast (HBL-100, T-47D) tumor cell lines. Bulbs and leaves were active in all cell lines (GI50 < 2.5 µg/mL). These findings suggest that the endemic Chilean plant P. cyrtanthoides contains diverse types of bioactive alkaloids with antiproliferative activities and inhibitory effects with potential therapeutic applications for neurodegenerative diseases

Comparison of characteristics and tumor targeting properties of extracellular vesicles derived from primary NK cells or NK-cell lines stimulated with IL-15 or IL-12/15/18

NK cell-based therapies have shown promise for hematological cancer forms, but their use against solid tumors is hampered by their poor ability to infiltrate the tumor. NK cells release extracellular vesicles (EVs) containing cytolytic proteins, indicating that NK-cell derived EVs may have therapeutic potential. In this study, we compared the tumor-targeting potential of EVs derived from either primary NK cells or the NK cell lines NK-92 and KHYG-1 cultured in IL-15 alone or in combination with IL-12 and IL-18. Primary NK cells were also stimulated through the activating receptor CD16. Tumor cell apoptosis was measured using a panel of human colon, melanoma, glioblastoma, prostate, breast, and ovarian tumor cell line spheroids. NK cells or NK-92 cells stimulated with IL-12, IL-15, and IL-18 generated EVs with higher efficiency than EVs from resting cells, although similar amounts of EVs were produced under both conditions. Proteomic analysis indicated similar distribution of cytolytic proteins in EVs from primary NK cells and NK-92, but lower levels in KHYG-1 EVs that translated into poor capacity for KHYG-1 EVs at targeting tumor cell lines. Further, we show that CD16-stimulated NK cells release low amounts of EVs devoid of cytolytic proteins. Importantly, EVs from cytokine-stimulated NK cells penetrate into the spheroid core, and tumor spheroid susceptibility to NK-cell derived EVs was linked to differential expression of the NKG2D ligands MICA/B, which was blocked with an anti-NKG2D antibody. We conclude that EVs from activated primary NK cells or NK-92 cells has the best potential to infiltrate and target solid tumors.

Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo.

Simple SummaryA key feature of human colorectal tumor is loss of FAS expression. FAS is the death receptor for FASL of activated T cells. Loss of FAS expression therefore may promote tumor cell immune escape. We aimed at determining whether restoring FAS expression is sufficient to suppress colorectal tumor growth. Mouse and human FAS cDNA was synthesized and encapsulated into cationic lipid nanoparticle DOTAP-Cholesterol to formulate DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Restoring FAS expression in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS+ tumor cells in vitro and suppressed colon-tumor growth and progression in tumor-bearing mice in vivo. Restoring FAS expression induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells in vitro. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. Tumor-selective delivery of FAS DNA nanoparticle is potentially an effective therapy for human colorectal cancer.A hallmark of human colorectal cancer is lost expression of FAS, the death receptor for FASL of cytotoxic T lymphocytes (CTLs). However, it is unknown whether restoring FAS expression alone is sufficient to suppress csolorectal-cancer development. The FAS promoter is hypermethylated and inversely correlated with FAS mRNA level in human colorectal carcinomas. Analysis of single-cell RNA-Seq datasets revealed that FAS is highly expressed in epithelial cells and immune cells but down-regulated in colon-tumor cells in human colorectal-cancer patients. Codon usage-optimized mouse and human FAS cDNA was designed, synthesized, and encapsulated into cationic lipid to formulate nanoparticle DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Overexpression of codon usage-optimized FAS in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS+ tumor cells in vitro, suppressed colon tumor growth, and increased the survival of tumor-bearing mice in vivo. Overexpression of codon-optimized FAS-induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. DOTAP-Chol-mFAS therapy exhibited no significant liver toxicity. Our data determined that tumor-selective delivery of FAS DNA nanoparticles is sufficient for suppression of human colon tumor growth in vivo.

Noninvasive Evaluation of EGFR Expression of Digestive Tumors Using 99mTc-MAG3-Cet-F(ab')2-Based SPECT/CT Imaging.

Purpose This study is aimed at investigating the feasibility of cetuximab (Cet) F(ab′)2 fragment- (Cet-F(ab′)2-) based single photon emission tomography/computed tomography (SPECT/CT) for assessing the epidermal growth factor receptor (EGFR) expression in digestive tumor mouse models. Methods Cet-F(ab′)2 was synthesized using immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) protease and purified with protein A beads. The product and its in vitro stability in normal saline and 1% bovine serum albumin were analyzed with sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The EGFR expression in the human colon tumor cell line HT29 and the human stomach tumor cell line MGC803 were verified using western blotting and immunocytochemistry. Cet-F(ab′)2 was conjugated with 5(6)-carboxytetramethylrhodamine succinimidyl ester to demonstrate its binding ability to the MGC803 and HT29 cells. Cet-F(ab′)2 was conjugated with NHS-MAG3 for 99mTc radiolabeling. The best imaging time was determined using a biodistribution assay at 1, 4, 16, and 24 h after injection of the 99mTc-MAG3-Cet-F(ab′)2 tracer. Furthermore, 99mTc-MAG3-Cet-F(ab′)2 SPECT/CT was performed on MGC803 and HT29 tumor-bearing nude mice. Results HT29 cells had low EGFR expression while MGC803 cell exhibited the high EGFR expression. Cet-F(ab′)2 and intact cetuximab showed similar high binding ability to MGC803 cells but not to HT29 cells. Cet-F(ab′)2 and 99mTc-MAG3-Cet-F(ab′)2 showed excellent in vitro stability. The biodistribution assay showed that the target to nontarget ratio was the highest at 16 h (17.29 ± 5.72, n = 4) after tracer injection. The 99mTc-MAG3-Cet-F(ab′)2-based SPECT/CT imaging revealed rapid and sustained tracer uptake in MGC803 tumors rather than in HT29 tumors with high image contrast, which was consistent with the results in vitro. Conclusion SPECT/CT imaging using 99mTc-MAG3-Cet-F(ab′)2 enables the evaluation of the EGFR expression in murine EGFR-positive tumors, indicating the potential utility for noninvasive evaluation of the EGFR expression in tumors.

ANTITUMOR EFFECT IN VIVO OF THE NEW PYRIDINE COMPOUND

Abstract. The study was the antitumor activity of a new compound - a pyridine derivative (LHT-13-19). On the culture of human colon cancer HCT116, the suppressive concentration of LHT-13-19 was determined during incubation of tumor cells in the concentration range from 10-9 to 10-7 M. The survival of tumor cells was also determined in the MTT test. Antitumor activity in vivo was studied on thirty athymic humanized 12-week-old female mice of the BALB / c nu / nu line with xenograft adenocarcinoma of the large intestine, divided into 3 groups, 10 mice each, which received intraperitoneal injections of 0.9% sodium chloride solution in a volume of 0.5 ml, cyclophosphamide at a dose of 10 mg / kg, LHT-13-19 at a daily dose of 3.7 mg / kg, respectively, for 10 days. Daily incubation of human colon tumor cells with LHT-13-19 is accompanied by the formation of the cytotoxic effect of the compound. In a xenograft model of colon adenocarcinoma, 10-day intraperitoneal administration of compound LHT-13-19 at a daily dose of 3.7 mg / kg was accompanied by the formation of an antitumor effect in the form of an increase in the doubling time of the tumor size, the survival rate of animals - carriers of xenograft, and a decrease in the frequency of metastasis. Keywords. Pyridine derivatives, LHT-13-19, cell culture, anticancer activity, inhibitory concentration

ON ANTITUMOR ACTIVITY OF A NOVEL COMPOUND – A PYRIDINE DERIVATIVE

The work studied the antitumor activity of a new compound, a pyridine derivative LHT-13-19. To determine the effective inhibitory concentration, a culture of human colon cancer HCT116 was used. Incubation of tumor cells was carried out in the presence of LHT-13-19 in the concentration range from 10-9 to 10-7 M. The survival of tumor cells was determined in MTT test. In vivo experiments were performed on thirty athymic humanized 12-week-old female BALB/c nu/nu mice with xenograft colorectal adenocarcinoma. All animals were divided into 3 groups, 10 mice in each: animals of the control group were injected daily intraperitoneally with 0.5 ml of PBS, animals of the second group were treated with a cyclophosphamide at a dose of 10 mg/kg, mice of the third the groups received LHT-13-19 as experimental therapy at a daily dose of 3.7 mg/kg during 10 days. Animals’ survival and antitumor activity were assessed. Tumor-doubling time, the number of liver superficial metastases and survival time were estimated. Daily incubation of human colon tumor cells with LHT-13-19 is accompanied by the formation of the cytotoxic effect of the compound. On a xenograft model of colon adenocarcinoma in humanized BALB/c nu/nu mice, a 10-day course of 3.7 mg/kg LHT-13-19 leads to the formation of an antitumor effect due to increase in the time of tumor doubling, animal survival and a decrease in the frequency of metastasis

Synthesis, crystal structure, DFT and anticancer study of dihydroartermisinin-paracetamol hybrids

A pair of C-10 epimers of dihydroartermisinin-paracetamol hybrids (A and B) were prepared in this work, and both of which were characterized by MS, 1H NMR, 13C NMR, IR and ECD spectra as well as by a single crystal X-ray structural analysis. Subsequently, the structures of the two compounds were analyzed with DFT-based approaches. The analytical results on conformations indicated that the DFT-optimized molecular structures were consistent with the crystal structures confirmed by X-ray diffraction. The packing of the molecules in the solid state was stabilized by hydrogen bonds. The signs of the experimental IR and ECD spectra was also efficiently simulated by the DFT methods. A primary evaluation on anticancer effects of A and B was conducted towards human breast tumor cell line MCF-7 and human colon tumor cell line HCT116, the results demonstrated that 10-α-O-(4-acetylamino) phenyl dihydroartemisinin (A) was slightly less potent than its 10-β counterpart (B) in both tested cell lines.

Antiproliferative Activity of Stokesia laevis Ethanolic Extract in Combination with Several Food-Related Bioactive Compounds; In Vitro (Caco-2) and In Silico Docking (TNKS1 and TNKS2) Studies

This study evaluates in vitro cytotoxic and antiproliferative activity on human colon tumor cell line Caco-2 (ATCC-HTB-37) of a standardized (5 mg GAE/mL) ethanolic extract from Stokesia laevis (Slae26), of five polyphenols compounds (reference substances, ref.), namely luteolin-7-O-glucoside, luteolin-8-C-glucoside, caffeic acid, gentisic acid, and p-aminobenzoic acid (PABA), as well as of Slae26 combinations with the five reference substances, 1:1 mass rate (GAE, ref.). Cell viability studies (MTS test) have revealed IC50 values of 36 μg GAE/mL in the case of Slae26 ethanolic extract, while Slae26 combinations with the five phenolics indicated IC50 values around 5 μg GAE/mL. In silico docking studies on the molecular targets human tankyrase 1 (TNKS1) and human tankyrase 2 (TNKS2) in complex with their native ligands, Co-crystallized 3J5A and Co-crystallized FLN, indicated score values of −104.15 and −76.97, respectively; in the series of the reference compounds studied, luteolin-7-O-glucoside was revealed with the best score values on both molecular targets (−80.49 and −85.17), together signifying real antiproliferative potential against human colon cancer of Slae26, of luteolin-7-O-glucoside, and of Slae26 combinations with all food-related bioactive compounds tested.

Antitumor Activity against Human Colorectal Adenocarcinoma of Silver Nanoparticles: Influence of [Ag]/[PVP] Ratio.

Silver nanoparticles (AgNPs) not only have shown remarkable results as antimicrobial and antiviral agents but also as antitumor agents. This work reports the complete characterization of five polyvinylpyrrolidone-coated AgNP (PVP-AgNP) formulations, their cytotoxic activity against human colon tumor cells (HCT-15), their cytotoxic effect on primary mouse cultures, and their lethal dose on BALB/c mice. The evaluated AgNP formulations have a composition within the ranges Ag: 1.14–1.32% w/w, PVP: 19.6–24.5% and H2O: 74.2–79.2% with predominant spherical shape within an average size range of 16–30 nm according to transmission electron microscopy (TEM). All formulations assessed increase mitochondrial ROS concentration and induce apoptosis as the leading death pathway on HCT-15 cells. Except for AgNP1, the growth inhibition potency of AgNP formulations of human colon tumor cancer cells (HCT-15) is 34.5 times higher than carboplatin, one of the first-line chemotherapy agents. Nevertheless, 5–10% of necrotic events, even at the lower concentration evaluated, were observed. The cytotoxic selectivity was confirmed by evaluating the cytotoxic effect on aorta, spleen, heart, liver, and kidney primary cultures from BALB/c mice. Despite the cytotoxic effects observed in vitro, the lethal dose and histopathological analysis showed the low toxicity of these formulations (all of them on Category 4 of the Globally Harmonized System of Classification and Labelling of Chemicals) and minor damage observed on analyzed organs. The results provide an additional example of the rational design of safety nanomaterials with antitumor potency and urge further experiments to complete the preclinical studies for these AgNP formulations.

Tumor-specific overexpression of histone gene, H3C14 in gastric cancer is mediated through EGFR-FOXC1 axis

Incorporation of different H3 histone isoforms/variants have been reported to differentially regulate gene expression via alteration in chromatin organization during diverse cellular processes. However, the differential expression of highly conserved histone H3.2 genes, H3C14 and H3C13 in human cancer has not been delineated. In this study, we investigated the expression of H3.2 genes in primary human gastric, brain, breast, colon, liver, and head and neck cancer tissues and tumor cell lines. The data showed overexpression of H3.2 transcripts in tumor samples and cell lines with respect to normal counterparts. Furthermore, TCGA data of individual and TCGA PANCAN cohort also showed significant up-regulation of H3.2 genes. Further, overexpressed H3C14 gene coding for H3.2 protein was regulated by FOXC1 transcription factor and G4-cassette in gastric cancer cell lines. Elevated expression of FOXC1 protein and transcripts were also observed in human gastric cancer samples and cell lines. Further, FOXC1 protein was predominantly localized in the nuclei of neoplastic gastric cells compared to normal counterpart. In continuation, studies with EGF induction, FOXC1 knockdown, and ChIP-qPCR for the first time identified a novel axis, EGFR-FOXC1-H3C14 for regulation of H3C14 gene overexpression in gastric cancer. Therefore, the changes the epigenomic landscape due to incorporation of differential expression H3 variant contributes to change in gene expression pattern and thereby contributing to pathogenesis of cancer.