HCT116 Research Articles

Pyrazole appended Schiff base based sensor for Al3+ detection: Spectroscopic investigation, real sample analysis and cell imaging studies

Herein, we are reporting a new pyrazole derived chemosensor named H2QPC [(E)-N’-((2-hydroxyquinolin-3-yl)methylene)-3-methyl-1H-pyrazole-5-carbohydrazide] exhibiting selective “off–on” fluorimetric response towards Al3+ ion in different solvents. The probe exhibited a submicromolar detection level (LOD = 0.37 μM) for the Al3+. The density functional theory (DFT) and time dependent DFT (TD-DFT) of the probe and corresponding Al3+-complex revealed that a change of structural conformation of probe H2QPC upon complexation. The pyrazole unit creates a specific cavity to tether Al3+, and consequently H2QPC shows as a promising molecule for Al3+ detection. Further, the probe has been used successfully for qualitative determination of Al3+ using filter paper strips. The in situ Al3+ ion cell imaging in HCT116 cells discloses the cellular penetrability of the sensor, and holds pronounced promise for application in biological and environment sciences.

A Tetranuclear copper(II) Complex with a Pyridine‐2,6‐dicarboxamide Ligand: Structural and Magnetic Properties and In vitro Antiproliferative Activity Against Human Cancer Cells

AbstractA pentadentate diamide ligand, N,N′‐di(pyridine‐2‐yl)pyridine‐2,6‐dicarboxamide (L1H2) and its tetranuclear Cu(II) complex [Cu4(L1)2(μ3‐OH)2(H2O)3(ClO4)](ClO4) ⋅ H2O are reported. X‐ray crystal structure of the complex reveals that it has an open‐book type architecture. Two central copper atoms are connected to each other by two hydroxo bridges. Each of these two hydroxo bridges also connects the two central copper atoms to one of the two terminal copper atoms. Variable temperature susceptibility measurements show that χMT decreases with the temperature, indicating a strong antiferromagnetic behavior. With the help of DFT calculations the magnetic data was analyzed using the spin Hamiltonian H=−2 J1S3 ⋅ S4 −2 J2(S3 ⋅ S1+ S3 ⋅ S2+ S4 ⋅ S1+ S4 ⋅ S2)−2 J3S1 ⋅ S2 (where subscripts 1 and 2 refer to the terminal copper atoms and 3 and 4 refer to the central copper atoms). The best fit was obtained with 2 J1=−322 cm−1, 2 J2=+34.8 cm−1, 2 J3=−8.8 cm−1 and g=2.18, indicating a δ‐type interaction between terminal copper atoms. The complex proves to be an avid binder of ct‐DNA, with apparent binding constant (Kapp) value estimated as 1.536×107 M−1. In vitro experiments indicate that the Cu(II) complex reduced the proliferation of HCT116 cells among other cell lines. This reduction of cell proliferation may be attributed to the enhancement of intracellular ROS, along with modulation and disruption of cell cycle associated proteins. SKC conceptualized the project, arranged funding and involved in overall coordination among collaborators, analyzing the data, and writing the paper. AM was involved in doing the experimental work on synthesis of the compounds, carrying out analytical and spectroscopic measurements, collecting X‐ray crystallographic data and DNA binding experiments. MS, SM and KDS were involved in study of anticancer activities of the complex. SS helped in refining X‐ray structure of the complex. MC did the magnetic measurements and analysis whereas AF did the DFT calculations.

Diphenyl urea-benzylidene acetohydrazide hybrids as fibroblast growth factor receptor1 inhibitors and anticancer agents.

Molecular hybridization between diphenyl urea and benzylidene acetohydrazide was adopted for the design of a new series of FGFR-1 targeting cancer. The designed series was synthesized and submitted to NCI-USA to be screened for their growth inhibitory activity on NCI cancer cell lines. Some of the synthesized hybrids displayed promising growth inhibitory activity on NCI cancer cell lines with a mean GI% between 70.39% and a lethal effect. Compounds 9a, 9i, 9j, and 9n-p were further selected for a five-dose assay and all the tested candidates showed promising antiproliferative activity with GI50 reaching the submicromolar range. Encouraged by the potent activity of 9a on colon cancer on the one hand and the well-known overexpression of FGFR-1 in it on the other hand, it was further selected as a representative example to be evaluated for its mechanism on the cell cycle and apoptosis of HCT116 cell line. Interestingly, 9a was found to pause the cell cycle of the HCT116 cell line at the G1 phase and induced late apoptosis. In parallel, all the synthesized hybrids 9a-p were examined for their potential to inhibit FGFR-1 at 10 µM. Compounds 9a, 9g, 9h, and 9p were found to have potent inhibitory activity with % inhibition = 63.04%, 58.31%, 60.87% and 79.84%, respectively. Molecular docking simulation of 9a in the binding pocket of FGFR-1 confirms its capability to achieve the characteristic interactions of the type II FGFR-1 inhibitors. Exploration of the ADME properties of 9a-p by SwissADME web tool proved their satisfactory physicochemical properties for the discovery of new anticancer hits.

Acquired Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Resistance of Human Colorectal Cancer Cells Is Linked to Histone Acetylation and Is Synergistically Ameliorated by Combination with HDAC Inhibitors.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive target for the treatment of various malignancies; however, its therapeutic potential is limited because of the frequent occurrence of tumor cell resistance. In this study, we determined whether TRAIL resistance acquired by repeated administration could be overcome by HDAC inhibition in human colorectal cancer cells. TRAIL-resistant HCT116 human colorectal cancer cells (HCT116-TR) were generated by repeated treatment with 10 and 25 ng/mL TRAIL twice weekly for 28 days. The resulting TRAIL-resistant cells were noncross-resistant to other chemotherapeutic agents. The levels of histone acetylation-related proteins, such as ac-histone H4 and HDAC1, were altered in HCT116-TR cells compared with the parental HCT116 cell line. The combined treatment with TRAIL and HDAC inhibitors significantly increased apoptosis in HCT116-TR cells and indicated a synergistic effect. The mechanism by which HDAC inhibition sensitizes HCT116-TR cells to TRAIL is dependent on the intrinsic pathway. In addition, we found that HDAC inhibition enhanced the sensitivity of cells to TRAIL through mitogen-activated protein kinases/CCAAT/enhancer-binding protein homologs of protein-dependent upregulation of death receptor 5. These results suggest that histone acetylation is responsible for acquired TRAIL resistance after repeated exposure and acquired resistance to TRAIL may be overcome by combination therapies with HDAC inhibitors.

CD11b/CD86 involved in the microenvironment of colorectal cancer by promoting Wnt signaling activation.

Colorectal cancer (CRC) is a malignancy that arises within the gastrointestinal tract. Despite ongoing research, the etiology and pathogenesis of CRC remain elusive; particularly, the distribution and characteristics of tumor-associated macrophages is currently an active area of investigation in understanding the pathological progression and prevention of CRC. This study utilized CRC patient surgical samples, mouse models of colitis-associated cancer, colonic organoid, and co-culture cell line to examine the changes in CD11b/CD86 at different pathological region and detect the Wnt signaling pathway activity. Our findings revealed a sensitive and increased expression of CD11b from the early to the advanced CRC tissues and correlated with poor prognosis, while CD86 expression was reduced in advanced CRC tissues. CD133 expression was also elevated in advanced CRC tissues and mainly co-localized with CD11b, suggesting a positive regulatory effect of CD11b and CD133 expression that may contribute to CRC progression. In AOM/DSS mouse models, activation of the Wnt signaling pathway was associated with increased CD133 and CD11b expression. Invitro, THP-1 cell was induced to high expression of CD11b, and the above conditional cultural medium enhanced HCT116 cell colony number and CD133 protein expression. Furthermore, colonic crypts from AOM/DSS mouse models were isolated to culture, and the colonic organoids exhibited dilation and significant increases expression of CD133 and β-Catenin/N-P-B-Catenin. CD11b might be an important factor to participate the progress of CRC. And the high CD11b of CRC microenviroment might potentially promote CD133 expression and associate with Wnt signal activation.

Silencing of KIAA1429, a N6-methyladenine methyltransferase, inhibits the progression of colon adenocarcinoma via blocking the hypoxia-inducible factor 1 signalling pathway.

KIAA1429 is an important 'writer' of the N6-methyladenine (m6A) modification, which is involved in tumour progression. This study was conducted to explore the mechanism of action of KIAA1429 in colon adenocarcinoma (COAD). KIAA1429-silenced COAD cell and xenograft tumour models were constructed, and the function of KIAA1429 was explored through a series of in vivo and in vitro assays. The downstream mechanisms of KIAA1429 were explored using transcriptome sequencing. Dimethyloxalylglycine (DMOG), an activator of HIF-1α, was used for feedback verification. The expression of KIAA1429 in COAD tumour tissues and cells was elevated, and KIAA1429 exhibited differential expression at different stages of the tumour. Silencing of KIAA1429 inhibited the proliferation, migration, and invasion of HT29 and HCT116 cells. The expression levels of NLRP3, GSDMD and Caspase-1 were decreased in KIAA1429-silenced HT29 cells, indicating the pyroptotic activity was inhibited. Additionally, KIAA1429 silencing inhibited the growth of tumour xenograft. Transcriptome sequencing and reverse transcription quantitative polymerase chain reaction revealed that after KIAA1429 silencing, the expression of AKR1C1, AKR1C2, AKR1C3 and RDH8 was elevated, and the expression of VIRMA, GINS1, VBP1 and ARF3 was decreased. In HT29 cells, KIAA1429 silencing blocked the HIF-1 signalling pathway, accompanied by the decrease in AKT1 and HIF-1α protein levels. The activation of HIF-1 signalling pathway, mediated by DMOG, reversed the antitumour role of KIAA1429 silencing. KIAA1429 silencing inhibits COAD development by blocking the HIF-1 signalling pathway.

In Silico Study, Synthesis and Evaluation of Cytotoxic Activity of New Sulfonamide-Isatin Derivatives as Carbonic Anhydrase Enzyme Inhibitors

Aim: Design, molecular docking, synthesis, and evaluation of cytotoxic activity of new compounds I, II, III, and IV that have isatin-sulfonamide derivatives. Materials and Methods: for chemical synthesis, chemical compounds such as sulfonamide, 4-amino ethyl benzoate, isatin, and its derivatives were used. For the docking study (MOE), software program version 2015.10 was used. The MTT assay was utilized to predict the cytotoxic activity. Results: The synthesized compounds demonstrated significant inhibition of carbonic anhydrase XII activity through molecular docking, as well as significant inhibition of cancer cell viability. Compounds II and IV show higher S-scores than acetazolamide. Also, the MTT assay shows that compounds II and IV have IC50 values of 0.06 µM and 0.105 µM against MCF-7 cells, respectively, while acetazolamide has an IC50 value of 0.394 µM. While acetazolamide had an IC50 of 0.901 µM, compounds II and IV had IC50s of 0.063 µM and 0.114 µM against Hct116 cells, respectively. The MTT assay explains compounds II and IV have better cytotoxic activity compared with acetazolamide. Conclusion: New compounds that were produced showed signs of cytotoxicity and carbonic anhydrase inhibitory qualities.

2-(3,4-dihydroxyphenyl)ethyl 3-hydroxybutanoate (HTHB) ameliorates cognitive dysfunction via modulating gut microbiota in aged senescence-accelerated mouse prone 8 (SAMP8) mice.

Numerous studies have indicated a close association between gut microbiota dysbiosis, inflammation, and cognitive impairment, highlighting their crucial role in the aging process. 2-(3,4-Dihydroxyphenyl)ethyl 3-hydroxybutanoate (HTHB), a novel derivative of hydroxytryrosol (HT), known for its metabolic and anti-inflammatory properties, was investigated for its effects on memory, inflammation, and gut microbiota in senescence-accelerated mouse prone 8 (SAMP8) mice. The study employed behavioral testing, biochemical detection and 16S RNA analysis. Results revealed that HTHB mitigated memory decline and lymphocyte aberrance, reduced inflammation in the brain cortex, intestine and peripheral system, and modulated gut microbiota dysbiosis. Interestingly, the cognitive function and serum inflammation of mice significantly correlated with differences in gut microbiota in SAMP8 mice. Furthermore, HTHB treatment exhibited an enhancement of gut barrier integrity in colon tissue in SAMP8 mice. In vitro experiments using HCT116 and DLD1 cells further evidenced that HTHB rescued the tight junction protein levels impaired by lipopolysaccharide (LPS). These finding demonstrate that HTHB effectively ameliorates cognitive dysfunction in aged mice, might by modulating gut microbiota, suppressing inflammation and promoting intestinal barrier integrity. This highlights the potential of HTHB as a therapeutic agent for age-related cognitive loss.

Targeted colorectal cancer treatment: In vitro anti-cancer effects of carnosine nanoparticles supported by agar and magnetic iron oxide

The usage of peptides in the colorectal cancer (CRC) treatment promises to be a new anti-cancer therapy with improved treatment efficacy. Carnosine, a natural dipeptide molecule, has been demonstrated to be a potential anti-cancer drug. Nonetheless, it shows an exhibition of high-water solubility and is quickly degraded by carnosinase. Meanwhile, agar and magnetic iron oxide are the most used materials for drug delivery due to some of their advantages such as the low cost and the larger biocompatibility feature. The purpose of this study was to investigate the anti-cancer ability of agar-encapsulated carnosine nanoparticles (AgCa-NPs) and agar-encapsulated carnosine nanoparticles-coated magnetic iron oxide nanoparticles (AgCaN-MNPs) in human CRC cells, HCT-116. We evaluated the effects of AgCa-NPs and AgCaN-MNPs with a variety of concentrations (0, 5, 10, 15, 30, 40, or 50 mM) on HCT-116 cells after 72 h and 96 h by using MTT assay and observation cell morphology. We then analyzed the cell cycle progression and assessed the expression changes of genes related to apoptosis, autophagy, necroptosis, and angiogenesis after treatment for 96 h. The results showed that AgCa-NPs and AgCaN-MNPs in vitro study decreased HCT-116 cells viability. This effect was attributed to arrest of cell cycle, induction of programmed cell death, and suppression of angiogenesis by AgCa-NPs and AgCaN-MNPs. These findings revealed the antitumor efficacy of AgCa-NPs or AgCaN-MNPs for CRC treatment.

Evaluation of newly synthesized 2-(thiophen-2-yl)-1H-indole derivatives as anticancer agents against HCT-116 cell proliferation via cell cycle arrest and down regulation of miR-25

In the present study, we prepared new sixteen different derivatives. The first series were prepared (methylene)bis(2-(thiophen-2-yl)-1H-indole) derivatives which have (indole and thiophene rings) by excellent yield from the reaction (2 mmol) 2-(thiophen-2-yl)-1H-indole and (1 mmol) from aldehyde. The second series were synthesized (2-(thiophen-2-yl)-1H-indol-3-yl) methyl) aniline derivatives at a relatively low yield from multicomponent reaction of three components 2-(thiophen-2-yl)-1H-indole, N-methylaniline and desired aldehydes. The anticancer effect of the newly synthesized derivatives was determined against different cancers, colon, lung, breast and skin. The counter screening was done against normal Epithelial cells (RPE-1). The effect on cell cycle and mechanisms underlying of the antitumor effect were also studied. All new compounds were initially tested at a single dose of 100 μg/ml against this panel of 5 human tumor cell lines indicated that the compounds under investigation exhibit selective cytotoxicity against HCT-116 cell line and compounds (4g, 4a, 4c) showed potent anticancer activity against HCT-116 cell line with the inhibitory concentration IC50 values were, 7.1±0.07, 10.5± 0.07 and 11.9± 0.05 μΜ/ml respectively. Also, the active derivatives caused cell cycle arrest at the S and G2/M phase with significant(p < 0.0001) increase in the expression levels of tumor suppressors miR-30C, and miR-107 and a tremendous decrease in oncogenic miR-25, IL-6 and C-Myc levels. It is to conclude that the anticancer activity could be through direct interaction with tumor cell DNA like S-phase-dependent chemotherapy drugs. Which can interact with DNA or block DNA synthesis such as doxorubicin, cisplatin, or 5-fluorouracil and which were highly effective in killing the cancer cells. This data ensures the efficiency of the 3 analogues on inducing cell cycle arrest and preventing cancer cell growth. The altered expressions explained the molecular mechanisms through which the newly synthesized analogues exert their anticancer action.

Antiangiogenic activity of 5-bromoindole carbothioamide derivative in ex vivo, in vivo, and in vitro experimental study

The study aimed to investigate the antiangiogenic, antioxidant, and cytotoxicity activity of a carbothioamide indole derivative. The 2-NPHC activity was evaluated using the ex vivo rat aorta ring assay, the in vivo chick chorioallantois membrane assay, the DPPH assay for scavenging activity, and the expression of the VEGF gene in colon cancer cell line (HCT116). The 2-NPHC had significant antiangiogenic activity in a dose-dependent manner in the rat aorta assay. 2-NPHC managed to reduce the DPPH free radical in a concentration-dependent, 2-NPHC had low to non-toxic effects on the HUVEC cell line, with an IC50 value of 711.7 μg/ml. The VEGF gene expression in the HCT116 cell line reduced the target gene expression compared to control cells. In conclusion, 2-NPHC exhibited significant inhibition of the angiogenesis process, either directly by inhibiting the release or activity of VEGF or indirectly through its antioxidant properties.

Short-chain fructooligosaccharides synthesis using a commercial enzyme complex from Aspergillus sp. and anti-cancer activity on HCT116 and HT-29 cell lines

Over the last years, short-chain fructooligosaccharides (FOS) have gained significant attention as valuable food and dietary supplement components. Apart from implications such as dietary fibres, sweeteners, and humectants, FOS are hailed for their prebiotic properties. Moreover, much research is dedicated to their role as anti-cancer agents. Despite the ongoing interest, both technical aspects, challenges of FOS production, and their anti-cancer role necessitate more in-depth investigations to understand their healthcare role better. This study aimed to optimise critical FOS synthesis parameters using a commercial enzyme, Viscozyme® L, to obtain a preparation with a high FOS content. A central composite design and response surface methodology evaluated the effect of pH, temperature, synthesis time, substrate, and enzyme load on multiple responses, chosen as independent variables, were utilised to define optimal conditions. Under the optimal conditions (temperature 50 °C, pH 5.5, sucrose concentration 352 g/L, enzyme concentration 2.5% v/v, and 5.5 h of reaction), a preparation with a total FOS content of 58.8% was obtained. The FOS preparation showed minimal in vitro antioxidant capacity in the ORAC, CUPRAC, and ABTS*+assays. In addition, the cytotoxicity of FOS against tested cell lines was evaluated. FOS did not reduce HT-29 cell viability even at the concentration of 2.5 mg/mL, whereas FOS inhibited the proliferation of HCT116 cells by 50% at 2.35 mg/mL. Finally, the sensitisation effect of FOS on HCT116 cell treatment with doxorubicin has been revealed.

Pharmacological investigation of new niclosamide-based isatin hybrids as antiproliferative, antioxidant, and apoptosis inducers

A group of Niclosamide-linked isatin hybrids (Xo, X1, and X2) was created and examined using IR, 1HNMR, 13C NMR, and mass spectrometry. These hybrids' cytotoxicity, antioxidant, cell cycle analysis, and apoptosis-inducing capabilities were identified. Using the SRB assay, their cytotoxicity against the human HCT-116, MCF-7, and HEPG-2 cancer cell lines, as well as VERO (African Green Monkey Kidney), was evaluated. Compound X1 was the most effective compound. In HCT-116 cells, compound X1 produced cell cycle arrest in the G1 phase, promoted cell death, and induced apoptosis through mitochondrial membrane potential breakdown in comparison to niclosamide and the control. Niclosamide and compound X1 reduced reactive oxygen species generation and modulated the gene expression of BAX, Bcl-2, Bcl-xL, and PAR-4 in comparison to the control. Docking modeling indicated their probable binding modalities with the XIAP BIR2 domain, which selectively binds caspase-3/7, and highlighted their structural drivers of activity for further optimization investigations. Computational in silico modeling of the new hybrids revealed that they presented acceptable physicochemical values as well as drug-like characteristics, which may introduce them as drug-like candidates. The study proved that compound X1 might be a novel candidate for the development of anticancer agents as it presents antiproliferative activity mediated by apoptosis.

Base-Mediated Chemodivergent [4 + 1] and [2 + 1] Cycloadditions of N-Alkylpyridiniums and Enones.

Divergent synthesis of structurally different products from the same kinds of starting materials is highly synthetically useful but very challenging. Herein, we reported a base-mediated chemodivergent [4 + 1] and [2 + 1] cycloaddition of N-alkylpyridinium and enone under mild conditions, leading to furan-fused bicycles with high diastereoselectivity and spirobicycles, respectively, from moderate to high yields. N-Alkylpyridinium salts were modular nucleophilic transfer reagents and C1 synthons, which underwent tandem Michael addition to the α,β-unsaturated ketones and cyclization under the base conditions. Late-stage derivatization of 4-propyldicyclohexylanone from an important industrial raw of liquid crystal display (LCD) screens was realized. In vitro, compound 3f exhibited good activities against human colon cancer cells (HCT116) with IC50 values in 9.82 ± 0.27 μM. Further biological evaluations investigated the mechanism of the effective inhibition of cell growth, including apoptosis ratio detection, cell cycle analysis, and migration capacity of HCT116 cells. In apoptosis effect studies, complex 3f increased the percentage of apoptotic HCT116 cells to 26.8% (15 μM).

Jiedu Xiaozheng Yin extract targets cancer stem cells by Wnt signaling pathway in colorectal cancer

Ethnopharmacological relevanceThe clinical application of the traditional Chinese medicinal formula Jiedu Xiaozheng Yin (JXY) for gastrointestinal tumors, particularly colorectal cancer (CRC), is well-established, yet the precise biological mechanism underlying its efficacy in CRC treatment remains elusive. Aims of the studyThis study endeavors to unravel the intricate mechanism through which JXY modulates colorectal cancer stem cells, thus elucidating the pathways by which it exerts its potent anti-tumor effects. Materials and methodsIn this study, the regulatory impact of JXY on the signaling pathway and function of CRC cells was analyzed through Network pharmacology. The ethyl acetate extract of JXY was detected the major compounds using HPLC and then treated the HCT-116 cells for RNA-Sequencing (RNA-Seq). Protein expression and stemness of HCT-15 and HCT-116 cells following JXY extract treatment were assessed using Western blot analysis and matrigel spheroid assays. Additionally, the β-catenin transcriptional activity was evaluated using a TOPflash reporter assay with or without Lithium chloride (LiCl) stimulation. Patient-derived organoids of CRC (CRC PDOs) were cultured using a stemness maintenance medium, and their viability was measured using ATP assays after treatment of JXY extract. Furthermore, the anti-tumor efficacy of JXY extract was assessed using a xenograft mice model derived from HCT-15 cells. ResultsNetwork pharmacology emphasized the influence of JXY on cancer stem cells and the Wnt signaling pathway. HPLC analysis confirmed that the JXY extract contained the three most prevalent pharmaceutical compounds among the four herbs documented in the Chinese Pharmacopoeia (rosmarinic acid, quercetin, and kaempferol). RNA-Seq results further elucidated the effect of JXY extract, particularly targeting cancer stem cells and the Wnt signaling pathway. Furthermore, JXY extract inhibited spheroid formation in CRC cells and downregulated CRC CSC markers (CD133, DCLK1, and C-MYC). Additionally, JXY extract suppressed the β-catenin expression and transcriptional activity as well as the Wnt pathway target proteins, including C-MYC and Cyclin D1. Consistent with findings from cell lines, JXY extract suppressed the growth of CRC PDOs exhibiting stemness characteristics. And JXY extract demonstrated a significant inhibitory effect on tumor growth, C-MYC, and β-catenin protein levels in xenograft tumors. ConclusionsThese results highlight the novel function of JXY extract in targeting CRC CSCs by regulating Wnt signaling pathway, underscoring its potential as a therapeutic agent for treating CRC.

Molecular characterization analysis of PANoptosis-related genes in colorectal cancer based on bioinformatic analysis.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and stands as the second principal contributor to cancer-related fatalities. Recently, emerging research has emphasized the role of pan apoptosis (PANoptosis) in tumor development and anti-tumor therapy. In the course of this investigation, we meticulously identified and conducted a correlation analysis between differentially expressed genes associated with PANoptosis in CRC (CPAN_DEGs) and the proportion of immune cells. Subsequently, we formulated a prognostic score based on the CPAN_DEGs. Further our analysis revealed a noteworthy reduction in UNC5D mRNA expression within HCT116, HT29 and SW480 cells, as validated by qRT-PCR assay. Furthermore, scrutinizing the TCGA database unveiled a distinctive trend wherein individuals with the low UNC5D expression exhibited significantly reduced overall survival compared to their counterparts with the high UNC5D levels. The drug susceptibility analysis of UNC5D was further performed, which showed that UNC5D was corassociated with the sensitivity of CRC to 6-Thioguanine. The outcomes of our investigation underscore the mechanisms by which PANoptosis influences immune dysregulation as well as prognostic outcome in CRC.

Enhancement of Cinnamomum camphora magnetic nanoparticle bioactivities via carboxymethyl cellulose immobilization for potential therapeutic applications in cancer treatment

A promising method for cancer therapy is the coating of magnetic nanoparticles with carboxy methylcellulose. In a research project, hydroalcoholic extract of Cinnamomum camphora leaves was used to demonstrate the production of magnetic nanoparticles (MNPs); MNPs were coated with carboxymethyl cellulose to form carboxymethyl cellulose-coated magnetic nanoparticles (CMNPs)were formed. Preliminary phytochemical screening of C. camphora confirmed the presence of flavonoids, carbohydrates, phenolic compounds, and proteins. Phenolics 280.59 (mg/g), flavonoids 15.46 (mg/g), proteins 1.9 (mg/mL) and total carbohydrates 293.80 (mg/g) were all quantified. To confirm the formation of MNPs and CMNPs, UV–visible (UV–vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS) were used. Peaks were observed at 232 nm and 240 nm, respectively. The largest absorption peaks were observed in MNPs and CMNPs, respectively. The particles were spherical in shape and less than 10 (nm) in diameter. The potential scavenging activity of biosynthesized MNPs and CMNPs was evaluated by the ABTS and DPPH assays, and the inhibition values IC50 were 141.3 ± 3.0 and 61.67 ± 2.5 (µg/mL) for ABTS and 176.1 ± 4.0 and 70.92 ± 3.0 (µg/mL) for DPPH, respectively (p ≤ 0.05). Furthermore, the cytotoxicity test results showed that the HCT-116 human colon cancer cell line had the lowest IC50 value of 20 (µg/mL) for CMNP, followed by the HepG2 hepatocellular carcinoma cell line with an IC50 value of 33 (µg/mL) for CMNP, indicating that the cytotoxic effect on colon cancer cells is stronger than on liver cancer cells. Molecular docking studies have revealed that CMNPs target and bind to apoptotic protein, enhancing their bioactivity and cytotoxic effects on cancer cells. Furthermore, our findings suggest that the induction of apoptosis may be responsible for the anticancer effects of CMNPs.Graphical abstract

Innovative Therapeutic Delivery of Metastasis-Associated in Colon Cancer 1-Suppressing miRNA Using High Transmembrane 4 L6 Family Member 5-Targeting Exosomes in Colorectal Cancer Mouse Models.

Elevated metastasis-associated in colon cancer 1 (MACC1) expression in colorectal cancer patients, and high transmembrane 4 L6 family member 5 (TM4SF5) protein expressed on various solid tumors' surface, are linked to aggressive cancer behavior and progression. In this study, adipose-derived stem cells (ASCs) were engineered to produce exosomes (Ex) that target the TM4SF5 protein on tumors. Moreover, MACC1-targeting microRNA was encapsulated within the Ex, resulting in TM4SF5-targeting Ex (MACC1-suppressing miRNA; miR-143). The anticancer effects of these Ex were investigated in vitro using the human colorectal cell line HCT116 and in vivo using colorectal cancer mouse xenograft models. In the in vivo assessment, administration of TM4SF5-targeting Ex[miR-143], referred to as tEx[miR-143] herein, resulted in the smallest tumor size, the lowest tumor growth rate, and the lightest excised tumors compared to other treatments (p < 0.05). It also led to the decreased expression of MACC-1 and anti-apoptotic markers MCL-1 and Bcl-xL while inducing the highest expression of pro-apoptotic markers BAX and BIM. These results were consistent with in vitro findings, where t Ex[miR-143] demonstrated the highest inhibition of HCT116 cell migration and invasion. These findings highlight the potential of tEx[miR-143] as an effective therapeutic strategy for colorectal cancer, demonstrating promising results in both targetability and anti-tumor effects in vitro and in vivo, warranting further investigation in clinical settings.

Fucoidan based polymeric nanoparticles encapsulating epirubicin: A novel and effective chemotherapeutic formulation against colorectal cancer

Colorectal cancer (CRC) is one of the most common and challenging malignancy that needs some effective and safer chemotherapeutic agents for the treatment. In this study, anticancer agent epirubicin (Epi) was loaded in polymeric polyethylene glycol-polylactic acid-nanoparticles (mPEG-PLA-NPs) coated with a marine anti-cancer non-toxic polysaccharide fucoidan (FC), to achieve a synergistic activity against CRC. The characterization of the NPs revealed that they were spherical, monodispersed, stable, with a negative zeta potential, and exhibited good biocompatibility and controlled release. In vitro anti-cancer activity of the NPs on HCT116 cell line was found to be promising, and corroborated well with in vivo studies involving BALB/C mice injected with C26 murine cancer cells. The outcome of MTT assay demonstrated that IC50 value of free Epi was 3.72 µM, and that of non-coated and coated Epi nano-formulations was 33.67 and 10.19 µM, respectively. Higher tumor regression, better survival and reduced off-side cardiotoxicity were observed when this novel NPs formulation was used to treat tumor-bearing mice. Free FC and Epi treated mice showed 37.73 % and 61.49 % regression in tumor size, whereas there was 79.76 % and 90.34 % tumor regression in mice treated with non-coated Epi NPs and coated Epi NPs, respectively. Therefore, mPEG-PLA-FC-Epi-NPs hold a potential to be used as an effective chemotherapeutic formulation against CRC, since it exhibited better efficacy and lower toxicity.

Novel gold-based complex GC7 suppresses cancer cell proliferation via impacting energy metabolism mediated by mitochondria

Due to their pivotal roles in regulating energy metabolism and apoptosis, mitochondria in cancer cells have been considered a vulnerable and feasible target. Many anticancer agents, e.g., metal-based compounds, are found to target and disturb mitochondria primarily, which may lead to the disturbance of energy metabolism and, more importantly, the initiation of apoptosis. In this work, a gold-based complex 7 (GC7) was synthesized and evaluated in a series of different cancer cell lines. The anticancer efficacies of GC7 on cell viability, apoptosis, and colony formation were determined. Cellular thioredoxin reductase (TrxR) activity, oxygen consumption rate (OCR), glucose uptake, and lactate production following GC7 treatment were evaluated and analyzed. The Jeko-1 and A549 xenograft models were used to assess GC7’s tumor-suppressing effects. The results showed that GC7 possessed a broad-spectrum anticancer effect, with IC50 values ranging from 0.43 to 1.2 μM in multiple cancer cell lines, which was more potent than gold-based auranofin (∼2–6 folds). GC7 (0.3 and 1 μM) efficiently induced apoptosis of Jeko-1, A549, and HCT116 cells, and it suppressed the sphere formation of cancer stem cells GSC11 and GSC23 cells at 0.1 μM, and it completely eliminated colony at 0.3 μM. The preliminary mechanistic study showed that GC7 inhibited cellular TrxR activity, suppressed mitochondrial OCR, reduced mitochondrial membrane potential (MMP), decreased glucose uptake, and possibly suppressed glycolysis to reduce lactate production. GC7 was predicted to have a similar yet slightly different pharmacokinetic profile as auranofin. Finally, GC7 (20 mg/kg, oral, 5/week, or 3 mg/kg, IP, 3/week) significantly inhibited tumor growth. In conclusion, GC7 showed great potential in suppressing cancer cell proliferation, probably via inhibiting TrxR and impacting mitochondria-mediated energy metabolism.