HCT116 Cell Lines Research Articles

Metabolomics and Anticancer Potential of the Aerial Parts of Dryopteris ramosa against Cancerous Cell Lines Assisted with Advanced Computational Approaches.

Dryopteris ramosa is a high-altitude plant of moist and shady habitat. Its aerial parts are edible and orally administered as an antibiotic and effective aphrodisiac. They are also used as pesticides, astringents, and febrifuges. The present study aimed to elucidate the plant's medicinal potential as an anticancer agent. Extracts of Dryopteris ramosa were examined for cytotoxic effects against AGS, A549, and HCT116 cell lines. The project also aimed to evaluate the phytochemical constitutents of the plant. For this purpose, GC-ToF-MS analysis was executed to identify the bioactive compounds in the aerial parts extract of Dryopteris ramosa. As a result, 93 different phytochemicals were identified from the spectral properties of GC-ToF-MS which contain 19 compounds of high peaks having reported anti-inflammatory, Anti-diabetic, Antibacterial, Analgesic, and antioxidant potential. Three different cell lines have been treated against Ethanol, Methanol, Ethyl acetate, Water, Chloroform, Acetone, and n-hexane extracts from the aerial parts of Dryopteris ramosa. These cell lines were checked and were ranked in lethality based on IC50 value. The extract samples were processed as serial dilution from high concentrations (500 ug/ml). All the three cell lines were treated for 48 hours. Extracts showed a significant effect in different cell lines (based on IC50 less than 200 ug/ml). Performing the in-vitro anticancer activity against the three different cell lines in Ethyl Acetate, Methanol, nhexane, Chloroform and Acetone extract of Dryopteris indicated that anticancer activity of the plant is high against AGS and A549 cell line while less prominent in HTC116 cell lines through MTT Assay. Insilico drug-likeness and ADMET analysis were studied of the compounds, that exhibit considerable drug likenesses, phytochemical medicinal chemistry, and a promising ADMET score and no toxicity. The candidate compounds were chosen for further elucidation by Molecular Docking and dynamic simulations. Employing the molecular docking approach for virtual screening of the phytochemicals it was found that the compounds Germacrene showed remarkable results towards BCL2 with -7Kcal/Mol and a-D-(+)-Xylopyranose showed significant docking results towards 5P21 with -7.1Kcal/Mol. For multi-scale frames structural aberrations and fluctuations identification of the docked complexes, a molecular dynamics analysis was performed for a 100 ps simulation run by accessing the online tool of MDweb simulations. These molecular docking and simulation analyses also revealed that both the phytochemicals have a stable interaction with the cancer-related proteins BCL2 and 5P21.

Investigating the combinatory effect of Sclerocarya birrea with doxorubicin against selected colorectal cancer cell lines.

Colorectal cancer incidences continue to increase annually, worldwide. Herbal plants with antiproliferative properties received research interest as agents that can be adjuvant therapies with chemotherapy drugs to enhance their efficacy and reverse drug resistance. Sclerocarya birrea ethanolic (SBE) and aqueous (SBW) extracts combined with doxorubicin (DOX) against drug-sensitive and drug-resistant colorectal cancer cells were investigated for their potential adjuvant and drug resistance reversal. The extracts were assessed for their potential anticancer activities on HCT15 and HT29 cell lines as well as their doxorubicin potentiating and drug resistance reversal effects respectively. The extracts were assessed for their cytotoxicity on normal 3T3-L1 fibroblast cells. Both SBE and SBW extracts exhibited no toxicity against normal 3T3 cells and showed low activity on the HT29 cell line. Contrarily, resistant HCT15 cells showed moderate to low activity with significantly higher inhibitory concentration (IC)50 values. The combination of SBE with DOX and SBW with DOX resulted in antagonistic interactions, causing an increase in IC50 values for HT29 and HCT15 cells. In contrast, the combination of DOX and verapamil (VER) produced an additive effect, with no change in their IC50 values. Based on the findings from the combination treatment, the SBE and SBW extracts demonstrated higher efficacy and synergistic effects combined with DOX at IC75 compared to the combination of DOX and VER, suggesting their potential as anticancer agents. However, further research on both the SBE and SBW extracts' mechanisms of action and in vivo effects is warranted.

Oxalis erythrorhiza Gillies ex Hooker et Arnott (Oxalidaceae): Chemical Analysis, Biological In Vitro and In Vivo Properties and Behavioral Effects

In this work, a decoction (DOe) and a methanolic global extract (MGEOe), obtained with the aerial parts of Oxalis erythrorhiza Gillies ex Hooker et Arnott (Oxalidaceae), were evaluated. The high-resolution liquid chromatography in conjunction with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) analysis showed forty compounds in MGEOe and twenty-nine in DOe, including flavones, C-glycosyl flavones, isoflavones, fatty acids, terpenes, phenolic acids, and sterols. The antioxidant properties were evaluated by DPPH, TEAC, FRAP, and ILP assays. Both DOe and MGEOe showed stronger antioxidant activities. The anti-inflammatory effects were evaluated by COX inhibition method, where DOe demonstrated a significant inhibitory effect. The cytotoxic effects were evaluated in the tumoral HCT-116 and non-tumoral HBL-100 cell lines, revealing a selective action from DOe and MGOe on cancer cells. DOe was evaluated in an animal model of insulin resistance, which is characterized by alterations in glucose and lipid metabolism, as well as cognitive impairments, including anxiety-like behavior and memory deficits. Male SD rats received sucrose (10% w/v, SUC), a half dilution of DOe (5% w/v) with sucrose (HDOeS) or DOe with sucrose (DOeS) from PND21 to PND61. Then, anxiety-like behavior and spatial memory were assessed using the open field (OF), elevated plus maze (EPM) and the novel object location (NOL) tests, respectively. Serum parameters basal glycemia, total cholesterol (TC) and tryglicerides were measured using commercial kits. The lipid peroxidation was determined in homogenates of cerebral cortex, hippocampus and hypothalamus by TBAR assay. Only HDOeS exhibited lower anxiety-like behavior in OF and improved performance in NOL compared to SUC. Furthermore, DOeS showed reduced serum parameters, while HDOeS presented lower TC levels than SUC. No differences were observed on TBAR assay. The beneficial properties of these preparations could be attributed to the identified metabolites. These findings highlighted O. erythrorhiza as a potential source of compounds to improve human health; however, further research is required to elucidate its mechanisms of action.

Differentiation-inducing factor-1 inhibits EMT by proteasomal degradation of TAZ and YAP in cervical and colon cancer cell lines.

We previously reported differentiation-inducing factor-1 (DIF-1) activated glycogen synthase kinase-3 (GSK-3) in various mammalian cells. GSK-3 has been proposed to regulate a number of signaling pathway including TAZ/YAP signaling pathway. To clarify the effect of DIF-1 on TAZ/YAP signaling pathway, we examined whether DIF-1 affect the expression levels of TAZ and YAP. We found that DIF-1-induced proteasomal- and GSK-3-dependent degradation of both TAZ and YAP in human cervical cancer cell line HeLa in a time- and dose-dependent manner. As TAZ/YAP signaling pathway is well known to accelerate the epithelial-mesenchymal transition (EMT) of the cancer cell, we examined the effect of TAZ/YAP signaling pathway on EMT-related proteins. Knockdown of TAZ and YAP proteins by siRNA significantly reduced the expression of fibronectin, vimentin, and Snail. We also found that DIF-1 suppressed the expression levels of TAZ/YAP target gene products and EMT-related protein. Further, overexpression of TAZ and YAP attenuated the inhibitory effects of DIF-1 on these protein expressions. Migration and trans-well invasion assays revealed that DIF-1 significantly inhibited HeLa cell migration and invasion. DIF-1-induced proteasomal- and GSK-3-dependent degradation of TAZ and YAP proteins and inhibition of cell migration and invasion were also observed in human colon cancer cell line HCT-116. These results suggest that DIF-1 inhibits the TAZ/YAP signaling pathway via GSK-3 activation. Further, it has been suggested that the inhibition of EMT induced by DIF-1 is involved with the suppression of TAZ/YAP signaling pathway.

Chlorhexidine Dihydrochloride Shows Anti-tumor Effects in Desmoid Tumors and Colorectal Cancer.

Desmoid tumors (DTs), or aggressive fibromatosis, are rare neoplasms arising from connective tissue, frequently exhibiting local invasiveness. The limited treatment options and high recurrence rates of DTs highlight the need for novel therapeutic strategies. This study investigated the efficacy of chlorhexidine dihydrochloride (CD) in inhibiting the growth of DTs and colorectal cancer (CRC). A mouse model with Apc mutations, specifically Apc1638N/+, was generated to study DTs. DT cells (Apc1638N+) (DTA) were collected from the mice for in vitro experiments. DTA were treated with CD, along with a CRC cell line (HCT-116), and tumor organoids derived from Apc1638N/+ mice. The effects of CD were assessed through cell viability assay (WST assay), colony formation assay, and cell migration assay. We tested the induction of cell apoptosis through caspase 3/7 activity assays and immunoblot analysis of cleaved-caspase 3 and cleaved-PARP1. Additionally, CD was tested for its anti-tumor efficacy using an in vivo CRC xenograft model with the HCT-116 cell line. CD significantly inhibited the viability, migration, and colony formation of DTA and CRC cells. It remarkably decreased the tumor growth in organoids derived from intestinal tumor cells in the Apc1638N/+ mouse model. Furthermore, CD showed anti-tumor effects in an in vivo CRC xenograft model using the HCT-116 cell line. CD represents a promising therapeutic strategy for treating both DTs and CRC.

Design, synthesis, biological evaluation and molecular docking study of novel quinolone derivatives as potent HDAC1 (Histone Deacetylase) inhibitors and anticancer agents

Histone deacetylases (HDACs), especially HDAC1, are attractive targets for anticancer drug design because of their significant role in transcriptional repression and chromatin remodeling. Benzamide groups are widely reported as the most effective zinc binding groups (ZBGs) in design of HDAC inhibitors. Quinolone derivatives, exhibiting various therapeutic effects, are attractive scaffolds for developing novel HDAC inhibitors with potentially supposed therapeutic profiles. To explore the potential of 4-quinolones as a novel scaffold for a cap of HDACis, 14 novel structures were rationally designed and synthesized. Four cancer cell lines (HCT116, HT29, MCF7, and A549) and one normal cell (CHO) were applied to investigate the cytotoxicity of synthesized compounds. Furthermore, the inhibitory activity of the synthesized compounds was analyzed against pan-HDAC isozymes (HDAC1, HDAC2, HDAC3 and HDAC6). Five compounds (5a, 5b, 5c, 5e and 5h) showed strong cytotoxicity and HDAC inhibition even superior to entinostat as the reference drug. Collectively, these results suggest that compounds with an electron-donating group at the positions 6 or 8 of the quinolone ring (cap) appear to enhance the anti-proliferative potency. After performing induce-fit docking (on HDAC1, 2, 3, 6) for all the synthesized compounds, a significant correlation was identified between the MTT results, the inhibitory activity of pan-HDAC, and the docking scores of HDAC1. Therefore, compounds 5e and 5a (the most potent compounds) were identified as the most favorable leads for further investigation of HDAC1-specific enzyme inhibition. Compounds 5a and 5e showed impressive HDAC1 inhibitory potency with IC50 values of 0.48 μM and 0.36 μM, respectively, equal or more than that of Entinostat. Compound 5e (3 µM) also exhibited significant induction of apoptosis in the HCT116 cell line (the percentage of apoptotic cells was 81.87%), even stronger than the reference drug Entinostat (the percentage of apoptotic cells was 37.5%) at the same concentration which is consistent with their antiproliferative activities as well. 100 ns molecular dynamic (MD) simulation revealed that compound 5e can form stable interactions with HDAC1 through coordination with zinc ion, strong hydrophobic interactions and formation of hydrogen bonds. These results suggested that compound 5e can be promising lead for further development of potent anticancer and HDAC inhibitor drugs.

Exploration of the key active ingredients and mechanisms of Sparganii Rhizoma-Curcumae Rhizoma compatible formulation against human colorectal cancer through network pharmacology and in vitro experiments

IntroductionSparganii Rhizoma-Curcumae Rhizoma (SR-CR) formulation may offer an effective treatment for human colorectal cancer (CRC). However, the active ingredients and underlying mechanisms of this herbal formulation remain unclear. MethodsThis study integrates network pharmacology, molecular docking and experimental verification to identify key active ingredients and elucidate the mechanisms of SR-CR in CRC treatment. ResultsTwenty-three active components of SR-CR were identified using the TCMSP, UniProt and Gene Cards databases. These components were associated with 178 targets, of which 118 are directly related to CRC. Protein-protein interaction (PPI) network analysis identified protein kinase B (AKT) 1, epidermal growth factor receptor (EGFR), SRC, Bcl2 and CASP3 as core anti-CRC targets. Gene Ontology (GO) and KEGG pathway analyses were performed on these 178 intersecting targets, and the results showed that these targets are involved in EGFR tyrosine kinase inhibitor resistance and AGE-RAGE signaling pathway in diabetic complications. At the same time, five compounds, including bisdemethoxycurcumin, formononetin, β-sitosterol, stigmasterol and hederagenin, were selected based on the target number of effective components and tested for cytotoxicity against human CRC cell lines HT-29, HCT-8 and HCT-116 in vitro. The results showed that bisdemethoxycurcumin exhibited significant anti-proliferative activity against HCT-116 cells. Molecular docking results indicated that bisdemethoxycurcumin effectively binds with AKT, EGFR, Bcl-2 and CASP3. Further pharmacological experiments demonstrated that bisdemethoxycurcumin inhibits HCT-116 cell proliferation and migration via inhibiting EGFR-AKT pathway, and induces apoptosis by up-regulating Bcl-2 expression. DiscussionBased on our study, inhibiting the EGFR-AKT pathway and upregulating Bcl2 may be one of the mechanisms by which SR-CR inhibits the growth of CRC. The main active ingredients of SR-CR include bisdemethoxycurcumin, formononetin, β-sitosterol, stigmasterol and hederagenin, which may exert anti-colon cancer activity by targeting the regulation of AKT, EGFR, Bcl-2 and CASP3. However, we need more in vitro and in vivo evidence to confirm this conclusion. This study lays the foundation for further research on the pharmacological mechanism of SR-CR in the treatment of CRC.

Anti-tumor Effects of Idarubicin Hydrochloride in Desmoid Tumors.

Desmoid tumors (DTs), also referred to as aggressive fibromatosis, originate from connective tissues and typically manifest with a propensity for local invasion. Despite extensive research efforts aimed at exploring novel anti-tumor agents for DTs, the development of effective clinical management strategies remains an ongoing challenge due to the limited success of current treatments, which frequently lead to inconsistent outcomes and a high recurrence rate of DTs. To overcome these limitations, we focused our research aim on a drug repositioning approach to identify existing medications that could be effective against DTs. Mouse models with Apc mutations, specifically Apc1638N/+ and Apc1638N/+/Trp53-/-, were generated to study DTs. Primary desmoid cells were isolated from these models for experimental analysis. Idarubicin hydrochloride (IDH), a topoisomerase II (TOPO II) inhibitor, was tested on these primary cells, colorectal cancer (CRC) cell lines, and tumor organoids derived from Apc1638N/+ mice. Cell viability was determined with the WST reagent and colony formation assay was evaluated. The anti-tumor efficacy of IDH was tested in an in vivo CRC xenograft model using HCT-116 cells. The TOPO II inhibitor IDH showed significant growth inhibition effects on Apc1638N/+ and Apc1638N/+/Trp53-/- cells. IDH also showed remarkable anti-tumor effects on CRC cell lines and tumor organoids derived from intestinal tumor cells of the Apc1638N/+ mouse model. Furthermore, IDH exerted dramatic anti-tumor effects on an HCT-116 cell line xenograft mouse model. IDH could be a promising therapeutic agent for inhibiting DTs and CRC by targeting TOPO II.

New 5, 6, 7, 8-Tetrahydro-Isoquinolines Bearing 2-Nitrophenyl Group Targeting RET Enzyme: Synthesis, Anticancer Activity, Apoptotic Induction and Cell Cycle Arrest.

In this work, we synthesized new 5, 6, 7, 8-tetrahydroisoquinolines and 6, 7, 8, 9-tetrahydrothieno[2, 3-c]isoquinolines derivatives, and the structures of these new compounds were confirmed with different spectroscopic techniques. Furthermore, the anticancer activities of these compounds were assessed against eight tumor cell lines and one normal human skin fibroblast cell line (HSF). Subsequently, IC50 values of the synthesized compounds were determined for two specific cancer cell lines. Compound 3 exhibited the most potent antiproliferative activity against the HEPG2 cell line, whereas compound 9c demonstrated superior efficacy against the HCT116 cell line. Moreover, the mechanism of action for compound 3 on HEPG2 cells using flow cytometry and Annexin V-FITC apoptosis analysis was studied. Compound 3 caused cell cycle arrest at the G2/M with a 50-fold increase in apoptosis of the HEPG2 cell line. Finally, a molecular docking study was conducted to assess the inhibitory potential of compounds 3 and 7 against the RET enzyme. Results indicated that compounds 3 and 7 bind to the RET enzyme with binding energies of -5.2 and -5.6kcal/mol, respectively. Although these values suggest inhibitory activity, they are less potent than the standard inhibitor, alectinib, which exhibits a binding energy of -7.2kcal/mol.

Organic Moiety on Sn(IV) Does Matter for In Vitro Mode of Action: nBu3Sn(IV) Compounds with Carboxylato N-Functionalized 2-Quinolones Induce Anoikis-like Cell Death in A375 Cells

Objectives: New tributyltin(IV) complexes containing the carboxylate ligands 3-(4-methyl-2-oxoquinolin-1(2H)-yl)propanoic acid (HL1) and 2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetic acid (HL2) have been synthesized. Methods: Their structures have been determined by elemental microanalysis, FT-IR and multinuclear NMR (1H, 13C and 119Sn) spectroscopy and X-ray diffraction study. A solution state NMR analysis reveals a four-coordinated tributyltin(IV) complex in non-polar solvents, while an X-Ray crystallographic analysis confirms a five-coordinated trigonal-bipyramidal geometry around the tin atom due to the formation of 1D chains. A theoretical structural analysis was performed by optimization employing B3LYP-D3BJ functional and 6-311++G(d,p)/def2-TZVP(Sn) basis sets for H, C, N, O/Sn, respectively. The interactions between tin(IV) and surrounding atoms were examined by QTAIM approach. The in vitro antiproliferative activity of the synthesized compounds was evaluated by MTT and CV assays versus MCF-7 (human breast adenocarcinoma), HCT116 (human colorectal carcinoma), A375 (human melanoma), 4T1 (mouse breast carcinoma), CT26 (mouse colon carcinoma) and B16 (mouse melanoma) tumor cell lines. Results: Both synthesized compounds (nBu3SnL1 and nBu3SnL2) exerted powerful micromolar IC50 cytotoxicity values and demonstrated high selectivity toward malignant cells. Both experimental drugs affected cell adhesion and induced anchorage independent apoptosis, a favorable type of cell death with an essential role in cancer dissemination prevention. The BSA-binding affinity of the obtained organotin compounds was followed by spectrofluorometric titration and molecular docking simulations. Conclusions: The tributyltin(IV) compounds selectively induce anoikis-like cell death in A375 cells, also highlighting the importance of the organic moiety on the tin(IV) ion in the mechanism of action.

Chitosomal Encapsulation Enhances the Anticancer Efficacy of a Theobromine Analogue: An Integrated In Silico and In Vitro Study

Aims: This study aims to prepare and investigate the potential of theobromine derivative-loaded chitosomes as an effective anticancer drug. Background: [Formula: see text]-Benzyl-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1[Formula: see text]-purin-1-yl)acetamide (T-1-BA) exhibited promising anticancer potential. Loaded chitosomes, highlighting their suitability as a drug delivery system. The study builds on the significance of targeted drug delivery systems for enhanced anticancer efficacy. Objectives: To prepare T-1-BA-loaded chitosomes (T-1-BA-PC-CS complex) using the thin film hydration technique. To examine the colloidal characteristics, entrapment efficiency, and stability of the T-1-BA-PC-CS complex. To assess the in vitro anticancer efficacy of the T-1-BA-PC-CS complex against Hct116 and A549 cancer cell lines comparing the free T-1-BA, blank chitosomes, and the standard EGFR inhibitor, Lapatinib. Methods: The T-1-BA-PC-CS complex was prepared through the thin film hydration technique. Colloidal characteristics, including particle size, PDI, and zeta potential, were examined. In vitro anticancer efficacy was assessed through IC[Formula: see text] values, comparative analyses, SI calculations, cell cycle analysis, flow cytometry, and wound healing assays. Results: The T-1-BA-PC-CS complex demonstrated reduced IC[Formula: see text] values against Hct116 and A549 cell lines, indicating enhanced cytotoxicity compared to free T-1-BA and blank chitosomes. Comparative analyses highlighted superior anticancer activity. SI values indicated preferential cytotoxic effects on cancer cell lines. Flow cytometry analysis revealed cell cycle alterations and increased apoptosis. Wound healing assays showed a significant impact on migration and wound healing in A549 cells. Conclusion: The findings suggest that the T-1-BA-PC-CS complex holds great promise as an anticancer therapeutic by efficiently inducing favorable alterations in cell cycle phases and apoptosis, demonstrating its potential for further development in cancer treatment.

IMPDH inhibitors upregulate PD-L1 in cancer cells without impairing immune checkpoint inhibitor efficacy.

Tumor cells are characterized by rapid proliferation. In order to provide purines for DNA and RNA synthesis, inosine 5'-monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo guanosine biosynthesis, is highly expressed in tumor cells. In this study we investigated whether IMPDH was involved in cancer immunoregulation. We revealed that the IMPDH inhibitors AVN944, MPA or ribavirin concentration-dependently upregulated PD-L1 expression in non-small cell lung cancer cell line NCI-H292. This effect was reproduced in other non-small cell lung cancer cell lines H460, H1299 and HCC827, colon cancer cell lines HT29, RKO and HCT116, as well as kidney cancer cell line Huh7. In NCI-H292 cells, we clarified that IMPDH inhibitors increased CD274 mRNA levels by enhancing CD274 mRNA stability. IMPDH inhibitors improved the affinity of the ARE-binding protein HuR for CD274 mRNA, thereby stabilizing CD274 mRNA. Guanosine supplementation abolished the IMPDH inhibitor-induced increase in PD-L1 expression. In CT26 and EMT6 tumor models used for ICIs based studies, we showed that despite its immunosuppressive properties, the IMPDH inhibitor mycophenolate mofetil did not reduce the clinical response of checkpoint inhibitors, representing an important clinical observation given that this class of drugs is approved for use in multiple diseases. We conclude that PD-L1 induction contributes to the immunosuppressive effect of IMPDH inhibitors. Furthermore, the IMPDH inhibitor mycophenolate mofetil does not antagonize immune checkpoint blockade.

Synthesis, mechanistic insights, and anticancer evaluation of novel 2-aroylbenzo[b]thiophen-3-ols: A DFT and Hirshfeld surface analysis

A simple one-pot reaction was employed for the synthesis of 2-aroylbenzo[b]thiophene derivatives by reacting 2-mercaptobenzoic acid with substituted bromomethyl aryl ketones in the presence of triethylamine and DMF in significant yield and purity. The structure of the product was elucidated through spectroscopic data and confirmed through single crystal X-ray diffraction data. The benzo[b]thiophene ring was found to be nearly coplanar with the adjacent carbonyl group and conformationally stabilized by intramolecular hydrogen bonding. The key intramolecular cyclization takes place via an in-situ generated enol, which is most likely formed and reacts at the carboxylic group mediated by the conjugate acid, triethylammonium bromide. Density functional theory (DFT) was employed to investigate the energy profile of the reaction at the B3LYP/6–31G(d,p) level. Finally, all the synthesized 2-aroylbenzo[b]thiophene-3-ols were screened in vitro against HCT116 (colorectal) and MCF-7 (breast) cancer cell lines at 25 μM and 50 μM treatments, indicating the antiproliferative potential of several derivatives.

Tryptamine-Derived Schiff Bases: Potent Antimicrobial Agents and Evaluation of Cytotoxicity, ADME and DNA Binding Properties.

Inspired by the fact that the introduction of indole pharmacophore in organic scaffolds could enable interesting pharmacological properties, the series of novel tryptamine-derived Schiff bases was synthetized. Tryptamine was used as a source of indole pattern, as well as an example of biogenic amines which chemical transformations lead to the compounds with prominent biological activities. The obtained results for antimicrobial activity against a range of bacterial and fungal strains and cytotoxic activities have revealed that Schiff base TSB4 combining the tryptamine and p-nitro aryl patterns in the structure showed better antifungal activity at low concentrations than standard drug Fluconazole, while compound TSB6 with molecular scaffold composed from tryptamine and quinoline moieties showed certain cytotoxic effect on HCT-116 cell line with a strongly expressed selectivity about healthy fibroblast cells, MRC-5. For these two selected compounds, additional ADME analysis and DNA interactions were performed. to obtain better insight into their pharmacokinetics and determination of binding mode for DNA molecules. As results suggested, strong binding of examined compounds to CT-DNA was observed, while the ADME screening showed that selected compounds possess suitable physicochemical properties for oral bioavailability and druglikeness.

In vitro antioxidant, anticancer and in silico studies of polyphenol enriched leaf extract of Asystasia gangetica

Polyphenols are natural biomolecules known for circumventing several diseases including cancer with little adverse effects. This study aimed to investigate the polyphenol enriched fractions from the leaf extract of Asystasia gangetica for their composition, biological activities such as antioxidant activity, haemolytic effects, and in vitro cytotoxicity against cancer cell lines. LC–MS/MS analysis of the enriched fractions identified a total of 35 distinct polyphenols with caffeic acid, luteolin, apigenin, and protocatechuic acid at higher concentrations. Fractions AG-3 and AG-4 exhibited the highest total antioxidant activity with higher concentration of phenolics and flavonoids. The AG-4 fraction had the highest levels of DPPH radical scavenging (IC50 = 32.74 µg mL-1) and ABTS radical scavenging (IC50 = 29.45 µg mL–1) activity, in addition to a modest iron chelating activity and reducing power. The fractions exhibited the least haemolytic activity. The cytotoxic potential of enriched fractions against the HCT-116, HeLa, PC-3, and HDF cell lines was further examined. While the extract showed no inhibitory effect on normal HDF cells, the cytotoxic activity of fractions on cell lines varied, with HCT-116 cells having the strongest anticancer activity with an IC50 of 43.82 µg mL–1. Additionally, fractions induced apoptotic activity in HCT-116 cells, resulting in cell cycle arrest at the G2M phase and an increase in sub-G0/G1 cells, with an IC50 of 13.54 µg mL–1 after 48 h of incubation. The in silico molecular docking of the active compounds against the TNIK receptor protein and ADMET (Absorption–Distribution–Metabolism–Excretion–Toxicity) characteristics are described. Overall, the study highlights the enhanced biological and antiproliferative activities of polyphenols in Asystasia gangetica leaf extract, which could be further utilized as a potential cancer treatment strategy.

Impact and mechanism study of dioscin on biological characteristics of colorectal cancer cells.

Colorectal cancer (CRC) is a considerable global health issue. Dioscin, a compound found in several medicinal plants, has shown potential anticancer effects. To find the relationship between CRC cells (HCT116) and diosgenin and clarified their mechanisms of action. CRC cell line HCT116 was cultured by dividing cells into control and dioscin groups (dioscin + Jagged 1 group; Jagged 1 group, 5 μg/mL; and dioscin group, 2.5 μg/mL). The dioscin groups were given different concentrations of dioscin. Cell Counting Kit-8 was chosen for testing cell viability in different groups. Flow cytometry was established to undiscover the apoptosis rate of human liver cancer cell line 11. Real-time PCR as well as Western blot analyses were applied to reveal the expression levels of caspase-3, Notch, and other proteins. Transwell and scratch experiments were conducted to assess cell migration and invasion abilities. This study indicated that dioscin restricted the growth of HCT116 cells, boosted cell apoptosis, and rose the Bax/Bcl-2 ratio as well as the expression of Caspase-3. Dioscin also inhibited physiological activities, for instance cell migration, and significantly reduced the expression levels of proteins for instance Notch1 (P < 0.05). Dioscin partially reversed the effects of Jagged 1. Dioscin exerts a certain inhibitory effect on HCT116, and its mechanism of action may be linked, with the inhibition of the Notch1 signaling pathway.

Discovery of New Immunomodulatory Anticancer Thalidomide Analogs: Design, Synthesis, Biological Evaluation and In Silico Studies.

New thalidomide analogs have been designed and synthesized by hybridizing the immunomodulatory gutarimide moiety with three antiproliferative nuclei: quinazolinedione, phthalazinedione, and quinoxalinone. The biological results revealed the strong impact of quinazoline derivatives 7a and 28, and phthalazine based 20a against HepG-2, MCF-7, PC3, and HCT-116 cell lines, compared to thalidomide. In particular, compound 20a was the most promising as it had far better biological activity than thalidomide with regard to inhibition of TNF-α, IL-6, caspase 3, COX-I/II, and VEGFR-2, as well as cell cycle arrest, and apoptosis rate enhancement in MCF-7 cells, the most sensitive cell line to the current new molecules. Compound 20a caused reduction in levels of TNF-α and IL-6 by 75.22% and 82.51%, respectively. It elevated the caspase-3 level by 7.21-fold. Furthermore, IC50 against COX-I, COX-II, and VEGFR-2 were 0.65 μM, 0.33 μM, and 232 nM, respectively. In addition, it raised the apoptosis rate from 65.65% to 99.89%. Moreover, 20a was further examined through a docking study and a 200 ns molecular dynamics simulation for its complex with VEGFR-2, along with computational ADME properties. This work suggests the high significance of compounds 20a, 7a and 28, as lead compounds for development of new effective immunomodulatory antitumor drugs.

Forced Overexpression and Knockout Analysis of SLC30A and SLC39A Family Genes Suggests Their Involvement in Establishing Resistance to Cisplatin in Human Cancer Cells.

The metabolism of zinc and manganese plays a pivotal role in cancer progression by mediating cancer cell growth and metastasis. The SLC30A family proteins SLC30A3 and SLC30A10 mediate the efflux of zinc, manganese, and probably other transition element ions outside the cytoplasm to the extracellular space or into intracellular membrane compartments. The SLC39A family members SLC39A8 and SLC39A14 are their functional antagonists that transfer these ions into the cytoplasm. Recently, the SLC30A10 gene was suggested as a promising methylation biomarker of colorectal cancer. Here, we investigated whether forced overexpression or inactivation of SLC30A and SLC39A family genes has an impact on the phenotype of cancer cells and their sensitivity to cancer therapeutics. In the human colon adenocarcinoma HCT-15 and duodenal adenocarcinoma HuTu80 cell lines, we generated clones with knockouts of the SLC39A8 and SLC39A14 genes and forced overexpression of the SLC30A3, SLC30A10, and SLC39A8 genes. Gene expression in the mutant and control cells was assessed by RNA sequencing. The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of SLC30A10 resulted in an ~2.7-4 times increased IC50 of cisplatin, and overexpression of SLC30A3 resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets.

Natural Products-Based Anticancer Agents: Synthesis and Anticancer Activities of Funtumine Amide/Sulfonamide Derivatives.

Funtumine is a pregnene-type steroidal alkaloid exhibiting moderate anticancer activity. To discover novel natural product-based anticancer drugs, a series of novel funtumine amide/sulfonamide derivatives were papered and identified using spectroscopic techniques. Additionally, the structures of compounds 2j, 3a, and 4k were further confirmed through X-ray diffraction analysis. Biological activity experiments conducted against three cancer cell lines revealed that several of the synthesized compounds demonstrated inhibition activities comparable to or exceeding those of the commercial anticancer agent, 5-Fluorouracil. Especially compound 4i demonstrated a notably strong growth inhibitory effect on HePG2 (IC50=14.89 μM) and HCT116 (IC50=15.67 μM) cell lines, while exhibiting minimal cytotoxicity towards human normal BEAS-2B cells. Preliminary structure-activity relationships (SARs) analysis indicated that the conversion of the carbonyl group at the C-20 position of funtumine to a hydroxyl group could yield more potent compounds.

Carborane Conjugates with Ibuprofen, Fenoprofen and Flurbiprofen: Synthesis, Characterization, COX Inhibition Potential and In Vitro Activity.

The most effective anticancer drugs currently entail substantial and formidable side effects, and resistance of tumors to chemotherapeutic agents is a further challenge. Thus, the search for new anticancer drugs as well as novel therapeutic methods is still extremely important. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit COX (cyclooxygenase), overexpressed in some tumors. Carboranes are emerging as promising pharmacophores. We have therefore combined both moieties in a single molecule to design drugs with a dual mode of action and enhanced effectiveness. The NSAIDs ibuprofen, flurbiprofen, and fenoprofen were connected with 1,2-dicarba-closo-dodecaborane(12) via methylene, ethylene or propylene spacers. Three sets of carborane-NSAID conjugates were synthesized and analyzed through multinuclear (1H, 11B, and 13C) NMR spectroscopy. Conjugates with methylene spacers exhibited the most potent COX inhibition potential, particularly conjugates with flurbiprofen and fenoprofen, displaying higher selectivity towards COX-1. Furthermore, conjugates with methylene and ethylene spacers were more efficient in suppressing the growth of human cancer cell lines than their propylene counterparts. The carborane-flurbiprofen conjugate with an ethylene spacer was the most efficient and selective toward the COX-2-negative cell line HCT116. Its mode of action was basically cytostatic with minor contribution of apoptotic cell death and dominance of cells trapped in the division process.