Search Results (1,314)

Cancer metastasis, characterized by the dissemination of malignant cells from the primary tumor to distant organs, remains the leading cause of cancer-related mortality in solid tumors. In colorectal cancer (CRC), increasing attention has been directed toward therapeutic strategies aimed at suppressing cancer cell migration and invasion rather than solely reducing tumor mass, giving rise to the concept of migrastatic therapies. In the present study, green-synthesized silver nanoparticles (AgNPs), previously obtained using aqueous extracts of Filipendula ulmaria (L.) Maxim. and Salvia verticillata L., were evaluated for their antimigratory and anti-inflammatory potential in human colorectal carcinoma HCT-116 cells. Treatment with AgNPs induced considerable perturbations in cellular redox homeostasis, as evidenced by increased intracellular reactive oxygen species (ROS), lipid peroxidation (LPO), glutathione (GSH), and nitric oxide (NO) levels. These redox alterations were accompanied by a significant inhibition of cancer cell migration, together with reduced expression of matrix metalloproteinases MMP-2 and MMP-9, key mediators of extracellular matrix remodeling associated with tumor progression. AgNP exposure was associated with activation of the cytoprotective transcription factor Nrf-2 and suppression of the pro-inflammatory NF-κB/COX-2 signaling axis, indicating coordinated modulation of redox-sensitive pathways linked to tumor cell motility and inflammatory responses. Collectively, these findings demonstrate that green-synthesized AgNPs derived from F. ulmaria and S. verticillata exert multi-level regulatory effects on redox balance, inflammatory signaling, and migration-associated molecular markers in colorectal cancer cells. This study supports their potential as promising migrastatic nanocarriers for further investigation in colorectal cancer research. Full article

Preclinical models play a critical role in the development of PSMA-targeted radiopharmaceuticals for prostate cancer. However, many existing models have practical limitations, including slow tumor growth, low engraftment rates, and restricted availability, and all human PSMA-positive lines are confined to immunodeficient hosts. We developed and characterized a novel PSMA-expressing transgenic cell line, CT26-PSMA, as a practical tool for preclinical screening of PSMA-targeting agents. The CT26-PSMA cell line was established by stable transfection of the murine colon carcinoma CT26 cell line with human PSMA using the Sleeping Beauty transposon system. PSMA expression was confirmed by RT-qPCR (reverse transcription quantitative polymerase chain reaction), flow cytometry, and radioligand saturation binding on intact cells. Two [⁶⁸Ga]Ga-labeled radioconjugates—the well-established PSMA-617 and a newly synthesized conjugate (Conjugate-1)—were used to validate the functionality of the model through in vitro binding, uptake and internalization studies, and through ex vivo biodistribution in CT26-PSMA tumor-bearing athymic male nu/nu mice. The CT26-PSMA cell line demonstrated high and stable PSMA expression, with approximately 95% of cells expressing the biomarker and no measurable loss over 16 passages in antibiotic-free medium. Saturation binding gave a receptor density of ~3.5 × 10⁶ sites per cell, approximately four-fold higher than that of LNCaP cells (~0.8 × 10⁶), with dissociation constants that were indistinguishable between the two radioconjugates and between the two cell lines (K_d 9.0–11.6 nM). Subcutaneous tumors reached ~300 mm³ within 8–10 days of inoculation, with a take rate of 10/10 versus 1/10 for LNCaP (Fisher’s exact test, p = 1.2 × 10⁻⁴). Both radiotracers showed saturable, 2-PMPA-blockable binding and uptake in CT26-PSMA cells, confirming the functional activity of the recombinant receptor. Biodistribution studies revealed accumulation of both conjugates in CT26-PSMA tumors, with generally comparable tumor-to-background profiles. The CT26-PSMA cell line represents a robust, rapid, and reproducible platform for preclinical evaluation of PSMA-targeting radiopharmaceuticals, and its murine BALB/c origin permits engraftment in immunocompetent or minimally immunosuppressed hosts, whereas existing human PSMA-positive lines do not. It is intended as a screening platform rather than as a model of prostate cancer biology. The validation data obtained with [⁶⁸Ga]Ga-labelled conjugates confirm the suitability of this cell line for future studies of PSMA-directed compounds. Full article

The underexplored Passerini–Smiles reaction (PSR), a variant of the 3-component Passerini reaction (3CPR), was successfully employed to create a tailored library of phenoxy-indoline carboxamide derivatives based on a fragment-based hybrid drug design strategy. Under mild conditions, inexpensive and commercially available isatin was utilized as a privileged carbonyl core, combined with electron-deficient phenols to establish a highly functionalized framework. Post-Passerini–Smiles transformations leveraged this strategic layout to provide a step-economical route to a complementary library of three-dimensional spirooxindole hybrids derived from the PS adducts. This study reinforces the relevance of combining structural hybridization with multicomponent reaction strategies in the discovery of potential anticancer active pharmaceutical ingredients (APIs). Both libraries were evaluated against six human solid-tumor cell lines, including non-small cell lung carcinoma, cervical and colon adenocarcinoma, and breast and pancreatic cancers. The most active compound 4gaa exhibited GI₅₀ values below 10 μM for most of the tested cancer cell lines. Full article

Background/Objectives: Filipendula ulmaria (L.) Maxim. (meadowsweet) is a medicinal plant traditionally used for its antioxidant and anti-inflammatory effects. There is also some data indicating its anticancer potential; however, its impact on colorectal cancer cells remains poorly understood. Here we investigated the cytotoxic and pro-apoptotic effects of an aqueous F. ulmaria extract on human LoVo colorectal cancer cells and analyzed some of the mechanisms underlying it. Methods: LoVo colorectal cancer cells were treated with the aqueous extract and analyzed for intracellular reactive oxygen species (ROS), mitochondrial membrane potential, DNA damage, lysosomal alterations, apoptosis-related mechanisms, and antioxidant activity. Phytochemical profiling was performed by HPLC-TOF/MS. Results: The extract elevated intracellular ROS levels, disrupted mitochondrial membrane potential, and induced DNA damage in LoVo cells. Activation of crucial caspases, along with increased p53 levels, confirmed engagement of both extrinsic and intrinsic apoptotic pathways. Changes in lysosomal fluorescence were also observed, indicating alterations in lysosomal properties. In chemical assays (FRAP, TAC, DPPH, ABTS, and superoxide scavenging), the extract demonstrated robust antioxidant capacity comparable to or exceeding that of ascorbic acid. Phytochemical profiling by HPLC-TOF/MS revealed a rich presence of bioactive flavonoids, phenolic acids, and coumarins. Altogether, our findings indicate that the extract’s cytotoxicity against colon cancer cells arises from a multifaceted mechanism involving oxidative stress, organelle dysfunction, and apoptosis induction. Conclusions: These results highlight F. ulmaria aqueous extract as a promising candidate for colorectal cancer phytotherapy as a form of supportive treatment and warrant further preclinical validation. Full article

Background/Objectives: Cadherin-17 (CDH17, LI-cadherin) is a non-classical cadherin with an atypical structure and unique functions. CDH17 expression is restricted to normal intestinal epithelium. Furthermore, CDH17 functions as an oncoprotein that promotes tumor migration and invasion in colorectal, gastric, and pancreatic cancers. Therefore, CDH17 is an important diagnostic marker and therapeutic target. The CDH17-directed strategies, including monoclonal antibodies (mAbs), bispecific Abs, antibody–drug conjugates (ADCs), and chimeric antigen receptor (CAR) T cells, have been evaluated in preclinical and clinical studies. Therefore, developing mAbs that specifically recognize cell surface-expressing CDH17 is essential for advancing both tumor diagnosis and therapy. Methods: Anti-human CDH17 mAbs (named Ca₁₇Mabs) were developed by immunizing a mouse with CDH17-overexpressed cells and a high-throughput screening using flow cytometry. Results: Among Ca₁₇Mabs, a clone, Ca₁₇Mab-5 (IgG₁, κ) specifically recognized CDH17-overexpressed Chinese hamster ovary-K1 (CHO/CDH17) cells with no detectable cross-reactivity to 21 other CDHs by flow cytometry. Ca₁₇Mab-5 also detected endogenous CDH17 in human colorectal cancer cell lines, COLO201 and COLO205. The apparent dissociation constant (K_D) values of Ca₁₇Mab-5 for CHO/CDH17 and COLO205 were estimated as 1.5 × 10⁻⁸ M and 1.3 × 10⁻⁸ M, respectively. Furthermore, Ca₁₇Mab-5 detected endogenous CDH17 by Western blotting. In immunohistochemistry, Ca₁₇Mab-5 exhibited clear membranous staining in normal colon epithelium, colorectal, gastric, and pancreatic cancers. Conclusions: Ca₁₇Mab-5 is a versatile tool for detecting CDH17 and has potential for tumor diagnosis. Full article

More than 20 years after the discovery of lunasin, a clear shift in lunasin research is observable—from an initial focus on its direct in vitro anticancer effects toward strategies aimed at improving its bioavailability and repositioning it as a potential adjunct in cancer therapy. Lunasin, a soy-derived bioactive peptide, has been extensively studied for its antineoplastic properties. However, its limited oral bioavailability restrains its efficacy in clinical trials. Therefore, recent research on lunasin points towards the possibility of using it as an adjunct in cancer treatment, rather than as a stand-alone nutraceutical in humans. In preclinical models, in vitro and in vivo, lunasin can enhance the effects of standard anticancer drugs in breast and colon cancers. Research suggests that lunasin can potentiate the effects of drugs, such as tamoxifen, aspirin, cisplatin, and oxaliplatin, by sensitizing cancer cells to apoptosis, modulating cell cycle progression, reducing metastatic potential, and attenuating drug-resistance pathways, including PI3K/Akt, FAK/MAPK1/NF-κB, and integrin-mediated signaling. In combination with those drugs, lunasin exerts significant anticancer effects at concentrations substantially lower than those proven as effective in monotherapy, suggesting a potential role in dose reduction in conventional agents and, subsequently, mitigation of their adverse effects. Although the enhanced effect of those combinations has been shown in preclinical models, there is a distinct lack of human clinical trials in this matter. Available evidence supports a promising concept of lunasin as a molecular “priming” agent that might complement cytotoxic therapies rather than replace them. This combination-oriented paradigm may represent a shift in lunasin research and offer a novel direction for the use of bioactive peptides in precision oncology; however, further studies exploring this possibility, including human clinical trials, are needed to elucidate lunasin’s role in nutraceutical-assisted cancer therapy. Full article

Tretinoin (all-trans-retinoic acid, ATRA) is an established therapy for acute promyelocytic leukemia (APL) and neuroblastoma (NB); however, its broader oncological application is limited by poor bioavailability and rapid resistance development. In this study, we developed lipidic ester derivatives of ATRA as a potential prodrug approach aimed at modulating its physicochemical and biological properties. Three ATRA derivatives were evaluated in vitro in six human cancer cell lines: leukemia (MV4-11), gastric (AGS), colon (HT-29), lung (A549), and breast cancer cells (MCF-7, MDA-MB-468). Cytotoxicity toward normal human breast epithelial cells (MCF-10A) was also assessed. Among the synthesized derivatives, cetyl all-trans-retinoate (ATRA-CA) exhibited the strongest anticancer activity, showing up to threefold greater potency than ATRA, with inhibitory concentrations ranging from 1.34 to 23.1 µM and minimal toxicity toward normal cells. Moreover, ATRA-CA enhanced the efficacy of conventional chemotherapeutics. In A549 cells, treatment with 5 and 10 µM ATRA-CA reduced the cisplatin IC₅₀ from 25.7 ± 3.2 µM to 9.1 ± 3.0 and 5.9 ± 1.5 µM, corresponding to synergistic (CI = 0.63) and additive (CI = 0.88) effects, respectively. Similar effects were observed in MCF-7 cells and in combination with doxorubicin and paclitaxel. Full article

Background/Objectives: The orphan nuclear receptors 4A1 (NR4A1) and NR4A2 are overexpressed in multiple solid tumors, and both receptors exhibit tumor promoter-like activities. A recent study reported that luteolin, a flavonoid that binds NR4A1, decreased the expression of the pro-oncogenic receptor tyrosine kinase MerTK in colon cancer cells. Methods/Results: In this study, we observed that MerTK protein was expressed in human SW480 and HCT116 and mouse CT26 colon cancer cell lines, and was significantly downregulated after treatment with 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) compounds, which are dual NR4A1/NR4A2 ligands. Moreover, knockdown of NR4A1 and NR4A2 also decreased MerTK protein expression and DIM-3,5 ligands, and receptor knockdown also decreased MerTK RNA levels expression. MerTK expression was also downregulated by knockdown of Sp1, Sp3, or Sp4 and by treatment with mithramycin. Subsequent studies using chromatin immunoprecipitation and transfection of a MERTK (promoter)–luciferase construct containing transcriptionally active GC-rich promoter elements indicated that MerTK expression in colon cancer cells was regulated by NR4A/Sp complexes, including NR4A1, NR4A2, Sp1, Sp3, and Sp4 transcription factors. Conclusions: The participation of NR4A1 and NR4A2 in the regulation of MerTK indicates that DIM-3,5 ligands represent a novel class of agents that can be used to inhibit MerTK expression in cancer cells by acting as dual NR4A1 and NR4A2 inverse agonists. Full article

Andean berry (Vaccinium meridionale Swartz) is an underutilized fruit that could serve as a source of bioactive compounds with biological properties associated with apoptosis and cytotoxicity in colorectal cancer cells. This study aimed to evaluate the cytotoxic and proapoptotic effects of Andean berry juice (ABJ) in human SW480 and SW620 colon cancer cell lines, which represent early-stage and metastatic colorectal cancer, respectively. The juice was prepared from freeze-dried fruits, and several concentrations were assayed in cells. Bioactive compounds in ABJ showed the strongest reductions in metabolic activity and proliferation observed in SW620 cells. ABJ treatments promoted early apoptosis while inducing cell cycle arrest in the S phase (SW480) and in the G2/M (SW620). Mild mitochondrial depolarization was observed, while increased reactive oxygen species (ROS) accumulation was detected in both cell lines. More proteins involved in the apoptotic process were modulated in SW620 cells, whereas SW480 displayed greater fold changes in regulatory and stress-response proteins. Proteomics and bioinformatics analyses suggested that extrinsic apoptosis predominated in SW480 cells, whereas intrinsic apoptosis was observed in SW620 cells. These results highlighted the cytotoxic and pro-apoptotic potential of the combined activity of polyphenolic compounds from ABJ, demonstrating distinct mechanisms in vitro. Full article

Lectins are carbohydrate-binding proteins, some of which exhibit significant anti-tumor activity. Siye is a lectin derived from the red alga Kappaphycus alvarezii that was previously discovered using an artificial intelligence-guided genome mining strategy and shown to exert cytotoxic effects against several human cancer cell lines, including breast adenocarcinoma HCC1937. Based on the presence of shared glycopatterns between breast and colon cancers, we hypothesized that Siye may also exhibit anti-tumor activity against colon cancer cells. The cytotoxic effect of Siye on human colon cancer HCT116 cells was evaluated using the CCK-8 assay. Apoptosis was assessed by flow cytometry with Annexin V-FITC/PI staining. Expression levels of apoptosis-related genes (Bax, Bcl-2, Casp3, Casp8, Casp9, and TP53) were determined by qRT-PCR. Competitive inhibition assays using mannan were performed to assess the role of cell surface glycan binding. Siye significantly reduced the viability of HCT116 cells in a dose-dependent manner, with an IC₅₀ value of 14.065 μg/mL (=0.488 μM). Flow cytometry revealed that Siye promoted both early and late apoptosis in HCT116 cells, whereas in HCC1937 cells, the effect was primarily on early apoptosis. Mechanistically, Siye significantly upregulated the expression of the pro-apoptotic genes Bax (p < 0.05) and Casp9 (p < 0.001) in HCT116 cells, while in HCC1937 cells, Casp9 expression was significantly increased (p < 0.001). Morphological changes, including cell rounding and agglutination, were observed within 4 h of Siye treatment in both cell lines and were attenuated by co-treatment with mannan, suggesting that Siye-induced morphological changes are associated with binding to cell surface glycans. This study suggests that the red algal lectin Siye exerts anti-tumor effects against colon cancer HCT116 cells by inducing caspase-associated apoptosis. The differential apoptotic response between HCC1937 and HCT116 cells suggests cell-type-specific mechanisms. These findings extend the known anti-tumor activity spectrum of AI-discovered red algal lectin Siye and provide a basis for further investigation of its glycan-associated cellular effects and marine drug discovery potential. Full article

Objectives: Curcumin possesses well-documented anticancer activity; however, its clinical translation is hindered by poor aqueous solubility and limited bioavailability. The present study aimed to engineer pH-dependent bovine serum albumin (BSA)–based nanocarriers for curcumin delivery and to evaluate their physicochemical characteristics, controlled release behavior under gastrointestinal pH conditions, and in vitro anticancer efficacy against the human colon cancer cell line Colo-205. Methods: Curcumin-loaded bovine serum albumin nanoparticles (Cu-BSA-NPs) were fabricated using a desolvation technique followed by chemical crosslinking. Particle size, zeta potential, and polydispersity index (PDI) were assessed by dynamic light scattering. Morphology was examined using scanning electron microscopy (SEM), while structural and thermal properties were evaluated by Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Drug loading capacity and entrapment efficiency were quantified spectrophotometrically. In vitro drug release was investigated using a gastrointestinal pH-transition model (pH 1.2, 6.8, and 7.4). Cytotoxic activity was assessed using the sulforhodamine B (SRB) assay on Colo-205 cells. Results: The engineered Cu-BSA-NPs exhibited particle sizes ranging from 96.7 ± 10.5 to 126.4 ± 35.8 nm, with PDI values between 0.289 and 0.581 and zeta potentials from −18.2 ± 1.01 to −34 ± 1.0 mV, indicating nanoscale dimensions and moderate colloidal stability. SEM analysis revealed spherical nanoparticles with smooth surfaces and uniform morphology. Entrapment efficiency ranged from 6.59 ± 1.11% to 52.98 ± 0.65%, while drug loading efficiency varied between 1.308 ± 0.206% and 16.744 ± 0.266%. In vitro release studies demonstrated minimal drug release under acidic (pH 1.2) and near-neutral (pH 6.8) conditions, followed by significantly enhanced release at pH 7.4, confirming pH-dependent behavior of the albumin matrix. Cytotoxicity studies showed significant antiproliferative activity against Colo-205 human colon cancer cells. Conclusions: The findings demonstrate successful engineering of albumin-based nanocarriers capable of modulating curcumin release under physiologically relevant pH conditions and enhancing in vitro anticancer activity. Although limited to in vitro evaluation, this study highlights the potential of protein-based nanoplatforms as adaptable delivery systems for colon cancer therapy. Further in vivo investigations are warranted to validate their translational and therapeutic potential. Full article

CXCL14 is a highly conserved chemokine with potential roles in tumor progression and immune modulation. This study investigates the functional impact of CXCL14 on colon cancer by exploring its effects on tumor cell behavior and the immune microenvironment. We generated stable cell lines overexpressing CXCL14 in mouse MC38 and CT26 cells and human HCT15 colon cancer cells, and used these models to assess tumor growth, invasion, and immune cell infiltration. Our results demonstrate that CXCL14 suppresses colon cancer cell proliferation, migration, and metastasis. In vitro, CXCL14 inhibited the expression of matrix metalloproteinases (MMPs), key regulators of epithelial–mesenchymal transition (EMT), suggesting a role in promoting mesenchymal–epithelial transition (MET). Additionally, in vivo studies using a subcutaneous tumor model showed that CXCL14 not only suppressed tumor growth but also enhanced the infiltration of immune cells, including NK cells, dendritic cells (DCs), and T cells, converting the tumor microenvironment from a “cold” to a “hot” phenotype. RNA sequencing and pathway analyses revealed that CXCL14 regulates the expression of genes associated with angiogenesis, immune response, and cell signaling, particularly through the MAPK pathway. Furthermore, CXCL14’s influence on tumor progression was confirmed in a spleen-to-liver metastasis model, where its overexpression reduced metastatic spread. In conclusion, CXCL14 inhibits colon cancer progression by modulating both tumor cell behavior and the immune landscape, making it a promising candidate for targeted immunotherapy. Our findings highlight CXCL14’s potential to enhance anti-tumor immunity and provide new insights into its therapeutic applications in colon cancer. Full article

Triple-negative breast cancer (TNBC) is one of the most aggressive and clinically challenging subtypes of breast cancer, defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. The lack of actionable molecular targets contributes to limited therapeutic options, frequent recurrence, and a high propensity for distant metastasis. Metastatic dissemination remains the principal cause of mortality in patients with TNBC and is driven by complex molecular mechanisms involving multiple interconnected signaling networks. This review summarizes current knowledge of the molecular mechanisms underlying metastatic progression in TNBC, with particular emphasis on signaling pathways that regulate tumor invasion, migration, and colonization of distant organs. We discuss the roles of key pathways, including PI3K/Akt, TGF-β, Wnt/β-catenin, NF-κB, and Rho/ROCK signaling, in the regulation of epithelial–mesenchymal transition, cytoskeletal remodeling, cancer stem cell phenotypes, and tumor–microenvironment interactions. A deeper understanding of these signaling networks may facilitate the identification of novel therapeutic targets and support the development of more effective strategies to limit metastatic disease in TNBC. Full article

Dysregulation of the immune system, gut microbiota alteration, and epithelial dynamics in the colon contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the role of epithelial dynamics, particularly epithelial regeneration, remains incompletely understood. CADM1 encodes an immunoglobulin-superfamily cell adhesion molecule involved in epithelial adhesion, immune cell interactions, and tumor suppression in colon and various cancers. Here, we investigated the role of CADM1 in IBD using a murine model of colitis induced by dextran sulfate sodium in both wild-type and conventional Cadm1-deficient (Cadm1^−/−) mice. Cadm1^−/− mice exhibited more severe colitis than wild-type mice with increased mortality (64% vs. 10%) and delayed recovery. Cadm1^−/− mice showed reduced numbers of Ki-67-positive cells in colonic crypts and delayed epithelial regeneration, whereas no significant differences were observed in epithelial apoptosis, intestinal permeability, or immune responses. Immunohistochemistry revealed that CADM1 expression was restricted to regenerative crypt cells in wild-type mice with nuclear accumulation of β-catenin and phospho-Akt. Furthermore, CADM1 overexpression in colon epithelial cells enhanced Tcf-transcriptional activity in a β-catenin-dependent manner. Immunohistochemistry of human IBD materials revealed that CADM1 expression also correlated with nuclear β-catenin accumulation in crypt epithelial cells. Collectively, CADM1 appears to promote colonic epithelial regeneration through the PI3K/Akt/β-catenin axis to protect against severe epithelial injury in IBD. Full article

Background/Objectives: Ribosome-inactivating proteins (RIPs) are plant-derived enzymes with potent cytotoxic activity, widely studied as anticancer agents, particularly as toxic payloads in immunoconjugates. Despite numerous encouraging results reported, their clinical application has been limited by their immunogenicity. RIPs from edible plants have been proposed as potentially more suitable candidates due to their possible improved tolerability. However, this aspect still requires validation in vivo in animal models. This study investigated the cytotoxic activity, mechanisms of action and translational potential of sodin 5 (a recently characterized type 1 RIP derived from the edible plant Salsola soda L.) in human colon cancer models, comparing it to the well-known type 1 RIP saporin-S6. Methods: The effects of sodin 5 and saporin-S6 on cell viability, cell death mechanisms and epithelial barrier integrity were assessed on HT29 and Caco-2 cell lines. Sodin 5 cross-reactivity with other anti-type 1 RIP sera was evaluated by ELISA. Finally, its structural characteristics were analyzed. Results: Sodin 5 showed a cytotoxic effect comparable to that of saporin-S6 in HT29 and Caco-2 colon cancer cells, with time- and concentration-dependent reductions in viability. Both type 1 RIPs disrupted the integrity of the intestinal epithelial barrier in mono- and co-culture models and predominantly activated the apoptotic pathway, without inducing necrosis. Sodin 5 exhibited limited immunological cross-reactivity and a conserved catalytic core, supporting its potential relevance as a therapeutic payload for intestinal cancer therapy. Conclusions: Our results indicate that sodin 5 possesses promising characteristics for anticancer applications, particularly in the treatment of intestinal malignancies, where local exposure and repeated administration are often required. Full article