Search Results (305)

γ-Tocotrienol (γ-T3), a naturally occurring vitamin E isoform from plant-derived sources, has attracted attention as an antitumour agent. However, whether γ-T3 can enhance antitumour immunity and improve immune checkpoint blockade remains unclear. Here, using colorectal cancer (CRC) models, we found that γ-T3 suppressed tumour growth in immunocompetent MC38 and CT26 mouse models, whereas this effect was markedly weakened in immunodeficient hosts, indicating that its in vivo antitumour activity is closely associated with host immunity. Combination treatment with γ-T3 and programmed cell death protein 1 (PD-1) blockade further improved tumour control, accompanied by enhanced CD8⁺ T cell effector function, reduced regulatory T cell abundance, and tumour-associated macrophage remodelling towards an antitumour phenotype. Immune cell depletion experiments confirmed that CD8⁺ T cells are the principal effector cells mediating γ-T3-associated tumour suppression. Mechanistically, HSPA4 was identified as a candidate γ-T3-associated protein potentially linked to MHC-I-related immune-recognition features. γ-T3 promoted the expression of Psmb8 and Tap2 and increased MHC-I surface levels on tumour cells, accompanied by increased sensitivity of tumour cells to activated CD8⁺ T cell-mediated growth inhibition. These findings support γ-T3 as a naturally derived immune-sensitising agent for improving PD-1 blockade therapy in CRC. Full article

Colorectal cancer (CRC) is intricately linked to gut microbiota dysbiosis and tryptophan (Trp) metabolic dysregulation. This study aimed to clarify the role and mechanisms of 20(S/R)-ginsenoside Rh1 in suppressing colorectal cancer through the regulation of gut microbiota and Trp metabolism. Azoxymethane/dextran sulfate sodium (AOM/DSS)was employed to induce a CRC mouse model, followed by treatment with 20(S/R)-ginsenoside Rh1 at 100 mg·kg⁻¹·day⁻¹ for 6 weeks. 20(S/R)-ginsenoside Rh1 significantly reduced the disease activity index (DAI) score, restored colon length, and decreased tumor count. 20(S/R)-Ginsenoside Rh1 ameliorated gut dysbiosis by increasing gut microbial diversity and elevating the prevalence of beneficial bacteria, including Lactobacillus, and stimulated the production of indole derivatives, including indole-3-propionic acid (IPA), indole-3-acetic acid (IAA), and indole-3-lactic acid (ILA) by enriching Trp -metabolizing bacteria such as Lactobacillus reuteri. These changes further activated the AhR/CYP1A1/IL-22 and PXR/TLR4 pathways, upregulated the expression of intestinal tight junction proteins, suppressed the secretion of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IFN-γ, and elevated the levels of the anti-inflammatory cytokine IL-10. Furthermore, 20(S/R)-ginsenoside Rh1 reduces the serum kynurenine (Kyn)/Trp ratio, downregulates the expression of forkhead box P3 (FoxP3), a marker of regulatory T (Treg) cells, and increases the number of CD8⁺ T cells by inhibiting the expression of indoleamine 2,3-dioxygenase 1 (IDO1) in colonic tissue. In conclusion, 20(S/R)-ginsenoside Rh1 showed potential anti-CRC activity, with our study observing links between its action and gut microbiota structure regulation, Trp metabolism modulation, AhR/PXR-mediated intestinal barrier activation, and IDO1-related immune suppression reversal. Full article

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with more than 90% patients dying from metastasis due to limited treatment options. Although miRNA-based therapeutics represent a promising strategy, their clinical application has been hindered by poor stability in vivo and the lack of efficient organ-specific delivery systems. Methods: In this study, we developed a lung-targeted lipid nanoparticle (LuT-LNP) platform for the delivery of a chemically modified miRNA, AM22, which demonstrated enhanced tumor-suppressive activity. By replacing cholesterol and helper lipids with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the most abundant lipid in pulmonary surfactant, and systematically optimizing the ratios of ionizable and cationic lipids, we obtained a LuT-LNP formulation with superior lung tropism. Results: The resulting LuT-LNPs exhibited excellent stability, biocompatibility, and efficient encapsulation and protection of AM22. Both in vitro and in vivo, AM22-loaded LuT-LNP (AM22@LuT-LNP) significantly inhibited the proliferation and migration of CRC cells and markedly suppressed lung metastasis in a mouse model. Mechanistic studies revealed that AM22 acts by targeting Poly (ADP-ribose) polymerase 1 (PARP1), inducing DNA damage, and inhibiting the epithelial-mesenchymal transition (EMT) process. Conclusions: These findings established a lung-targeted delivery platform for miRNA-based therapy, offering a promising strategy for the treatment of colorectal cancer pulmonary metastasis (CRPM). Full article

Cancer remains a leading cause of mortality worldwide, largely due to dysregulated apoptotic signaling and the persistent activation of oncogenic pathways. However, natural products are a promising source of multi-target anticancer agents. In this study, we investigated the anticancer activity and underlying mechanisms of Clausena harmandiana root extract and its major carbazole alkaloid, 7-methoxyheptaphylline, both in vitro and in vivo. High-Performance Liquid Chromatography (HPLC) chemical fingerprinting confirmed the presence of bioactive coumarins and carbazole alkaloids in the extract. Cytotoxicity assays demonstrated that the extract significantly reduced the viability of human colorectal adenocarcinoma (HT-29), human hepatocellular carcinoma (HepG2), human lung adenocarcinoma (A549–Luc2), and murine Lewis lung carcinoma (3LL–Luc2) cells in a dose- and time-dependent manner. Our mechanistic investigations revealed the activation of JNK signaling, downregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1), and increased cleaved caspase-3 expression, indicating that mitochondrial apoptosis was induced. Notably, 7-methoxyheptaphylline markedly suppressed STAT3 phosphorylation in a concentration-dependent manner, comparable to the STAT3 inhibitor JSI-124. In a syngeneic 3LL–Luciferase2 lung cancer mouse model, oral administration of C. harmandiana capsules significantly reduced tumor growth and bioluminescence intensity compared with controls. These in vivo findings were consistent with the inhibition of STAT3 signaling and induction of apoptosis observed in vitro. Collectively, our results demonstrate that C. harmandiana exerts broad-spectrum anticancer activity through coordinated modulation of the JNK–STAT3 axis, leading to caspase-dependent apoptosis. These findings highlight its potential as a promising candidate for the development of STAT3-targeted anticancer therapies. Full article

Lung cancer is a leading cause of death worldwide and is often accompanied by declines in musculoskeletal health (i.e., cachexia). Despite affecting a majority of lung cancer patients, cachexia remains understudied and currently has no cure. We have previously demonstrated that liver metastases (LMs) exacerbate cachexia in murine models of colorectal cancer, and, while the liver represents a common site of metastases and is associated with poor prognosis in patients with lung cancer, whether LMs heighten musculoskeletal wasting in mice bearing lung cancer is unknown. Here, we aimed to characterize the impact of LMs on musculoskeletal health in a mouse model of lung cancer cachexia. C57BL/6J male mice were injected with LLC tumor cells either subcutaneously or intrasplenically (LMs) to mimic hepatic metastases (n = 6–9/group). Upon sacrifice, skeletal muscle, bone, and plasma were collected for morphological and molecular analyses. Consistently, compared to healthy controls, metastatic tumor hosts displayed greater reductions in muscle weights (~17%), in line with decreased muscle torque (~23%) and reduced muscle cross-sectional area (~10%). On a molecular level, skeletal muscle from mice bearing LMs had elevated levels of pStat3, Murf1, and Atrogin-1, suggesting enhanced protein catabolism. Similar to skeletal muscle, metastatic tumor hosts displayed greater losses in trabecular bone and increased skeletal fragility. Plasma proteomics identified 211 and 131 differentially expressed proteins in metastatic hosts compared to control animals and subcutaneous LLC hosts, respectively. Top regulated pathways in mice bearing LMs included neutrophil degranulation, BAG2 signaling, and cachexia signaling. Overall, our findings demonstrate that LMs are accompanied by accelerated musculoskeletal wasting and weakness in a mouse model of lung cancer cachexia. This work highlights the need for animal models that mimic advanced cancer, thus providing a better understanding of the mechanisms that mediate cachexia. Full article

Background: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), increase colorectal cancer (CRC) risk. Methods: Mouse IBD and CRC models with a combination of pharmacological, knockout and knock-in approaches was employed to analyze the involvement of TOP2s and NOS2 in CRC tumorigenesis. Key pathologies, such as inflammatory and neoplastic scores, were examined by immunohistochemical assays. Results: In colon tissues from acute, chronic colitis and CRC mouse models and from CD patients, the biomarkers γH2AX and 53BP1_pS25/S29 of DNA breaks (mainly representing DSBs) accumulated, alongside increases in topoisomerase II (TOP2) and nitric oxide synthase 2 (NOS2). Genetic ablation of NOS2 (Nos2^-/-) or TOP2β (Top2β^f/f) as well as pharmacological inhibition with ICRF-193 (a TOP2 inhibitor) or PTIO (a NO scavenger) reduced DSB formation and disease severity. Consistently, Nos2^-/-, or ICRF-treated, mice exhibited decreased tumor burden. DSBs and tumor accumulation were pronounced in the distal colon, mirroring human CRC distribution. While ICRF-193 suppressed tumor growth, Top2β^f/f deficiency (with a compensatory TOP2α upregulation) enhanced tumor development, indicating potential roles for TOP2 isozymes in tumor formation and progression. Conclusion: Collectively, these findings identify the cooperative action of TOP2 and NOS2 in driving DSBs, highlighting a potential therapeutic target in inflammation-associated CRC. Full article

Colorectal cancer (CRC) is a digestive tract malignant tumor with a relatively high incidence and mortality rate worldwide. The occurrence and development of CRC are closely associated with disturbances in the gut microbiota. Paraclostridium tenue (synonym Eubacterium tenue) is generally considered a harmless commensal and can be isolated from fecal samples of healthy adults. However, whether this bacterium is a beneficial organism with an antitumor effect is unknown. This study systematically evaluated the anti-CRC effects of P. tenue strain Pt517 on CRC cells in vitro and in the CT26 syngeneic mouse model. Pt517 culture supernatant (Pt517CS) inhibited the proliferation, colony formation, and migration ability of CRC cells; induced cell apoptosis; and altered cell cycle distribution. Daily intragastric administration of Pt517 significantly inhibited tumor growth in mice; increased the expression levels of TNF-α, INF-γ, and CD8 in tumor tissues; and decreased the levels of IL-6, IL-10, and TGF-β. Pt517 intervention significantly modulated the gut microbiota composition with increased relative abundance of Parabacteroides goldsteinii, Lachnospiraceae, and Enterorhabdus caecimuris B7. The long-chain fatty acids (LCFAs), stearic acid and palmitic acid, were increased in the serum of treatment group mice and detected in Pt517CS. Functional verification indicated that stearic acid and palmitic acid directly inhibited the proliferation of CT26 cells in a dose-dependent manner, suggesting that Pt517 might exert its anti-CRC effect by secreting LCFAs. These findings indicate that P. tenue Pt517 is a potential new candidate for the microbial treatment of CRC, which warrants further validation for its safety and efficacy before clinical translation. Full article

Background: Colorectal intraepithelial neoplasia (CR-EN) is a precursor lesion of colitis-associated colorectal cancer (CAC). This study investigated the interventional effects and molecular mechanisms of Rhapontici Radix extract on CR-EN. Methods: An azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model of colonic intraepithelial neoplasia, bioinformatics analysis, organoid models, and HCT116 cell experiments were employed, coupled with histopathological examination, inflammatory cytokine detection, Western blot, immunofluorescence, and HPLC-MS/MS. Results: The results showed that the YAP/AKT-PI3K signaling pathway is aberrantly activated in CRC. Rhapontici Radix extract ameliorated colonic pathology, suppressed inflammatory responses, and remodeled gut microbiota composition in model mice. The extract selectively inhibited the proliferation of CR-EN organoids by downregulating Ki67 and β-catenin while upregulating p53, and suppressed the proliferation, colony formation, and migration of HCT116 cells. Mechanistically, the extract modulated the YAP/PI3K/AKT pathway by upregulating phosphorylated YAP (p-YAP) and downregulating phosphorylated AKT (p-AKT), phosphorylated PI3K (p-PI3K), and their downstream targets p-SRC and c-MYC. Conclusions: This study suggests that Rhapontici Radix extract intervenes in inflammation-associated carcinogenesis through a multi-pathway, multi-target strategy, offering potential therapeutic targets for CAC prevention and treatment. Full article

Colorectal cancer (CRC), characterized by epidermal growth factor receptor (EGFR) overexpression, is often associated with poor prognosis and limited therapeutic response to conventional chemotherapy. In this study, we developed EGFR-targeted extracellular vesicles (EGFR-tEVs) by transiently engineering donor cells to display the GE11 peptide, aiming to enhance the precision of doxorubicin (Dox) delivery. The physicochemical properties of EGFR-tEVs were characterized using TEM, NTA, and Western blot. In vitro, EGFR-tEV-Dox exhibited increased cellular uptake in EGFR-overexpressing HCT-116 cells, leading to the activation of the p53-Bax-cleaved PARP1 apoptotic pathway. Notably, while Dox treatment induced p53 in normal colon fibroblasts (CCD18-Co), it did not trigger significant Bax activation or PARP1 cleavage, suggesting a preference for survival-related signaling in non-malignant cells. In a xenograft mouse model, EGFR-tEVs + Dox administration resulted in a 33.1% reduction in tumor volume and an 82.8% decrease in Ki-67 expression compared to the control group. These results indicate that transient receptor-mediated targeting enhances functional drug delivery to malignant tissues while minimizing pro-apoptotic induction in normal cells. Our findings suggest that EGFR-tEVs + Dox represents a balanced therapeutic strategy that improves antitumor efficacy with a favorable safety profile for EGFR-positive colorectal cancer. Full article

Erythropoietin-producing hepatocellular receptor A2 (EphA2) has emerged as a key mediator that promotes tumor malignant progression. EphA2 overexpression and its non-canonical signaling lead to oncogenic transformation, metabolic reprogramming, resistance to treatments, and metastasis. Therefore, strategies targeting EphA2 have been evaluated in clinical trials. However, the clinical effects were not sufficient. An anti-EphA2 monoclonal antibody (mAb), Ea₂Mab-7 (mouse IgG₁, κ), demonstrated high affinity and specificity among Eph receptors. In this study, we produced recombinant class-switched Ea₂Mab-7 variants, including Ea₂Mab-7-mG_2a (mouse IgG_2a) and Ea₂Mab-7-hG₁ (human IgG₁). Both Ea₂Mab-7-mG_2a and Ea₂Mab-7-hG₁ recognized human triple-negative breast cancer MDA-MB-231, pancreatic cancer MIA PaCa-2, and colorectal cancer HCT-15 in flow cytometry. Furthermore, both Ea₂Mab-7-mG_2a and Ea₂Mab-7-hG₁ exerted significant antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against these tumors. In mouse xenograft models of breast, pancreatic, and colorectal cancers, both mAbs demonstrated antitumor activity. These results indicate the potential of Ea₂Mab-7 variants for the treatment of EphA2-positive cancers. Full article

5-Fluorouracil (5-FU) remains a cornerstone chemotherapeutic for colorectal cancer, exerting its antitumor effects primarily through disruption of DNA and RNA synthesis and subsequent induction of apoptosis. Nonetheless, its clinical efficacy is often compromised by prominent adverse effects, particularly mucositis. This study examines the potential of brown-strain Flammulina velutipes Singer (FVB) to alleviate 5-FU-associated intestinal damage in a mouse model, offering insights into its possible role in mitigating chemotherapy-induced toxicity. 5-FU treatment significantly exacerbated gastrointestinal toxicity, as evidenced by severe diarrhea, shortened colon length, villus atrophy, and architectural disorganization of the intestine. It also inhibited crypt cell proliferation and induced body weight loss. Mechanistically, 5-FU activated pro-inflammatory, apoptotic, oxidative stress, and EMT pathways and disrupted mucosal tight junctions. Notably, FVB administration mitigated these pathological changes, indicating its protective role against 5-FU-induced intestinal injury. In summary, this investigation presents novel evidence for the protective role of FVB in mitigating 5-FU-induced intestinal mucositis. The results highlight the therapeutic potential of FVB as an adjunct to chemotherapy, potentially reducing treatment-related toxicity and enhancing the clinical care and quality of life of individuals undergoing colorectal cancer therapy. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, necessitating the development of novel multi-targeted therapeutic agents. This study investigates the anticancer effects of Panax notoginseng extract (PNE) against CRC using an integrative approach of network pharmacology and experimental validation. Phytochemical profiling via LC–MS identified major ginsenosides, including Rb1, Rg1, and Rd. Network pharmacology analysis revealed potential targets such as Bcl-xL, STAT3/CDK1, and IL-2, which are associated with apoptosis, cell cycle regulation, and immune modulation, respectively. Experimental results demonstrated that PNE significantly inhibited the proliferation of HCT 116 and HT-29 CRC cells, induced G0/G1 phase arrest by modulating CDK4/6 and p21/p27, and promoted apoptosis by regulating BCL2 family proteins. Furthermore, PNE treatment suppressed tumor growth in a CT26-bearing syngeneic mouse model. These findings highlight that PNE exerts potent anticancer effects through multi-pathway modulation, suggesting its potential as a therapeutic candidate for CRC. Full article

Background: Exploring new management and treatment strategies for inoperable colorectal cancer is key to improving patient prognosis. Nanotechnology combining medical imaging with cancer treatment provides a new solution for the management of advanced cancer. Methods: This study designed and synthesized the dual-modal molecular imaging probe MnS@Tf-¹²⁵I and evaluated its diagnostic and therapeutic applications in colorectal cancer with high expression of transferrin receptors (TfR) through in vitro and in vivo studies. Results: The MnS@Tf synthesized in this study can release manganese ions for chemodynamic therapy (CDT) and magnetic resonance imaging (MRI) and can be combined with hydrogen sulfide (H₂S) for gas therapy in response to the acidic tumor microenvironment. The molecular imaging probe MnS@Tf-¹²⁵I was labeled with ¹²⁵I to verify MnS@Tf’s targeting and high affinity for tumors with high expression of TfR through in vitro experiments. In vitro cell experiments demonstrated the killing effect of MnS@Tf on CT26 cells. The results of blood clearance and imaging after intravenous injection of MnS@Tf-¹²⁵I showed that MnS@Tf could stably exert targeted tumor-killing effects in mice over an extended period. In vivo experiments indicated that MnS@Tf not only effectively initiated T1-weighted MRI but also significantly inhibited tumor growth in CT26-bearing mouse models. Conclusions: The dual-modal molecular imaging probe MnS@Tf synthesized in this study can specifically target tumors with high expression of TfR and has good therapeutic effects both in vitro and in vivo, indicating that the nanocluster has broad application prospects in clinical tumor management. Full article

Oxygen nanobubble (NBO₂) water is reportedly a promising therapeutic and radiosensitizing agent against solid cancers. However, the significance of nanobubble size in inflammation-associated colorectal carcinogenesis in vivo remains elusive. We investigated whether small NBO₂ water exerts stronger preventive effects against colitis and colorectal carcinogenesis in an azoxymethane/dextran sulfate sodium–induced mouse model of colitis-associated cancer. Differences in particle size between the small and large NBO₂ water samples were confirmed by atomic force microscopy. The mice received drinking water containing either small or large sized NBO₂ throughout the experiment. Small NBO₂ water significantly reduced disease activity index scores, histopathological colitis scores, colonic shortening, CD68-positive inflammatory macrophage density, and tumor numbers. However, body weight, water intake, food intake, and spleen weight were unaffected. Immunohistochemistry revealed that small NBO₂ water reduced the percentage of Ki-67-positive tumor cells and the proportions of hypoxia-inducible factor-1α–positive epithelial and stromal cells, whereas no significant differences were observed in CD8- or forkhead box P3-positive cells. We conclude that nanometer-sized oxygen bubbles prevent inflammation-associated colorectal carcinogenesis, and that particle size is a critical determinant of biological effects. Small amounts of NBO₂ water may help control colitis and tumor development by alleviating hypoxia in the tumor microenvironment. Full article

Chronic inflammation-driven colorectal cancer (CRC) is critically mediated by interleukin-17A (IL-17A)-dependent immune responses and nuclear factor-κB (NF-κB) signaling, which promote immune cell infiltration and tumor progression. In this study, the anti-tumor efficacy and molecular mechanisms of a standardized extract of Hedyotis diffusa Willd. (HD) and its constituent, ferulic acid (FA), were investigated using an azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated CRC mouse model. HD and FA treatment markedly alleviated colitis, reduced tumor number and size, improved survival, and attenuated histopathological damage. Transcriptomic analysis revealed significant modulation of immune-related pathways, with prominent suppression of IL-17A and NF-κB signaling. Molecular docking demonstrated binding of FA to IL-17A at Pro59 and Arg101, suggesting potential disruption of the IL-17A/IL-17RA interaction. Consistently, both HD and FA reduced immune cell infiltration, downregulated IL-17A production, and inhibited NF-κB activation in colonic tissues. Collectively, these findings demonstrated that HD exerted protective effects against inflammation-associated CRC through targeting the IL-17A/IL-17RA axis and downstream NF-κB signaling, providing mechanistic insight into IL-17A-centered immunomodulation in colorectal tumorigenesis. Full article