Tumor Suppressive Effects Research Articles

Concurrent Amplification of Ferroptosis and Immune System Activation Via Nanomedicine-Mediated Radiosensitization for Triple-Negative Breast Cancer Therapy.

Radiation therapy (RT) is one of the core therapies for current cancer management. However, the emergence of radioresistance has become a major cause of radiotherapy failure and disease progression. Therefore, overcoming radioresistance to achieve highly effective treatment for refractory tumors is significant yet challenging. Here, pH-responsive DSPE-PEoz modified hollow Bi2Se3-RSL3/diABZi (DP-HBN/RA) nanomedicine is designed as a radiation sensitizer for efficient treatment of triple-negative breast cancer by simultaneously amplifying ferroptosis and immune system activation. DP-HBN/RA can efficiently concentrate X-ray radiation energy inside the tumor, thereby promoting precise ionizing radiation exposure in tumor cells to produce large amounts of reactive oxygen species (ROS), leading to lipid peroxidation-induced ferroptosis. Meanwhile, ferroptotic cell death is intensified through the inactivation of GPX4 by RSL3 released from DP-HBN/RA to acidic conditions in the tumor microenvironment. Additionally, DP-HBN/RA enhances RT efficacy to exacerbate unrepairable DNA damage and release DNA fragments that activate the cGAS-STING signal pathway, evoking a systematic immune response. Ingeniously, the released diABZi reinforces cGAS-STING activation to boost the immunology antitumor effect. This work links the induction of ferroptosis and the initiation of systematic immune response to achieve highly effective tumor suppression, which opens up new avenues for future treatments of refractory tumors.

Anti-Tumor Effects of Vespa bicolor Venom on Liver Cancer: In Vitro and In Vivo Studies.

Despite the popular belief in the anti-tumor properties of Vespa bicolor venom (VBV), there is limited scientific evidence to support this claim. This study is the first to examine the anti-tumor effects of VBV on liver cancer, both alone and in combination with cisplatin (DDP), through in vitro and in vivo experiments. In vitro experiments evaluated VBV and its combination with DDP on HepG2 cell proliferation, invasion, migration, and apoptosis. Animal studies examined the tumor-suppressive effects, safety (hepatotoxicity and nephrotoxicity), and immune impact of these treatments in tumor-bearing mice. VBV monotherapy significantly inhibited the growth of HepG2 cells by suppressing their proliferation and invasion and induced apoptosis in vitro. Notably, low VBV concentrations significantly promoted the proliferation of normal liver cells (L-02), suggesting a hepatoprotective effect. In vivo, VBV monotherapy enhanced immune function and exhibited tumor suppression comparable to DDP monotherapy but did not induce significant liver or kidney damage. In addition, VBV combined with DDP synergistically enhanced the anti-tumor effects of DDP, compensating for its limited apoptosis-inducing activity and insufficient enhancement of immune function. Initial studies have shown the strong potential of VBV as an anti-liver-tumor drug, highlighting its unique clinical value.

The oncogenic lncRNA MIR503HG suppresses cellular senescence counteracting supraphysiological androgen treatment in prostate cancer

BackgroundThe androgen receptor (AR), a ligand-dependent transcription factor, plays a key role in regulating prostate cancer (PCa) growth. The novel bipolar androgen therapy (BAT) uses supraphysiological androgen levels (SAL) that suppresses growth of PCa cells and induces cellular senescence functioning as a tumor suppressive mechanism. The role of long non-coding RNAs (lncRNAs) in the regulation of SAL-mediated senescence remains unclear. This study focuses on the SAL-repressed lncRNA MIR503HG, examining its involvement in androgen-controlled cellular senescence in PCa.MethodsTranscriptome and ChIP-Seq analyses of PCa cells treated with SAL were conducted to identify SAL-downregulated lncRNAs. Expression levels of MIR503HG were analyzed in 691 PCa patient tumor samples, mouse xenograft tumors and treated patient-derived xenografts. Knockdown and overexpression experiments were performed to assess the role of MIR503HG in cellular senescence and proliferation using senescence-associated β-Gal assays, qRT-PCRs, and Western blotting. The activity of MIR503HG was confirmed in PCa tumor spheroids.ResultsA large patient cohort analysis shows that MIR503HG is overexpressed in metastatic PCa and is associated with reduced patient survival, indicating its potential oncogenic role. Notably, SAL treatment suppresses MIR503HG expression across four different PCa cell lines and patient-derived xenografts but interestingly not in the senescence-resistant LNCaP Abl EnzaR cells. Functional assays reveal that MIR503HG promotes PCa cell proliferation and inhibits SAL-mediated cellular senescence, partly through miR-424-5p. Mechanistic analyses and rescue experiments indicate that MIR503HG regulates the AKT-p70S6K and the p15INK4b-pRb pathway. Reduced expression of MIR503HG by SAL or knockdown resulted in decreased BRCA2 levels suggesting a role in DNA repair mechanisms and potential implications for PARP inhibitor sensitivity by SAL used in BAT clinical trial.ConclusionsThe lncRNA MIR503HG acts as an oncogenic regulator in PCa by repressing cellular senescence. SAL-induced suppression of MIR503HG enhances the tumor-suppressive effects of AR signaling, suggesting that MIR503HG could serve as a biomarker for BAT responsiveness and as a target for combination therapies with PARP inhibitors.

Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy

BackgroundTransmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD).ObjectiveWe aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in...

AMBRA1 drives gastric cancer progression through regulation of tumor plasticity

BackgroundStomach adenocarcinoma (STAD) is an aggressive malignancy characterized by high tumor plasticity and heterogeneity. This study investigates the role of Autophagy and Beclin 1 Regulator 1 (AMBRA1) in regulating tumor plasticity in STAD progression.MethodsCombined with clinical data, the pan-cancer analysis of AMBRA1 was performed to analyze the role of AMBRA1 in STAD. Western blot, Flow Cytometry (FCM) assay, trans-well assay, wound healing assay, MTT, Reactive Oxygen Species (ROS) assay, Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) and staining were performed to study the effects of AMBRA1 in AGS human gastric cancer cells. An AGS gastric cancer xenograft model was constructed to further verify the role of AMBRA1 in the development of STAD.ResultsAMBRA1 overexpression correlated with poor overall survival in STAD and was positively associated with T cell CD4+ infiltration. High AMBRA1 expression also indicated worse prognosis in patients with high cancer-associated fibroblast infiltration. AMBRA1 depletion suppressed STAD cell proliferation, migration, and invasion in vitro. Mechanistically, AMBRA1 knockdown induced G1/S cell cycle arrest and triggered cellular senescence through epigenetic alterations, including changes in H3K9me3 levels. AMBRA1 inhibition also sensitized STAD cells to chemotherapeutic agents. In vivo studies confirmed the tumor-suppressive effects of AMBRA1 loss, resulting in reduced tumor growth and increased cellular senescence.ConclusionsOur findings uncover an oncogenic role for AMBRA1 in STAD. Targeting AMBRA1 may induce tumor cell senescence, apoptosis, and potentiate anti-tumor immunity, providing a rationale for developing AMBRA1-targeted precision therapies to improve clinical outcomes in STAD patients.

Controlled Synthesis of the FeB Nanometallic Glasses with Stronger Electron Donating Capability to Activate Molecular Oxygen for the Enhanced Ferroptosis Therapy.

Considering the strong electron-donating ability and the superior biocompatibility, the integration of zero-valent iron nanostructure Fe0 (electron-reservoir) and zero-valent boron nanostructure B0 offers great promise for fabricating novel ferroptosis nanoagents. Nevertheless, the controlled and facile synthesis of alloyed Fe0 and B0 nanostructure-FeB nanometallic glasses (NMGs) has remained a long-standing challenge. Herein, a complexion-reduction strategy is proposed for the controlled synthesis of FeB NMGs with greater electron donating capacity to activate the molecular oxygen for improved ferroptosis therapy. In-depth mechanism reveales that the complexion-reduction strategy effectively prevent the long-range diffusion of Fe0, resulting in the amorphous alloyed Fe0 and B0 nanostructure-FeB nanoparticles (FeB NPs). The FeB NPs display stronger electron donating capability and electron transfer rate 9.4 times higher than that of the Fe0 NPs, which effectively activate the molecular oxygen to produce ∙O2 -, H2O2 and ∙OH. The in vitro cellular experiments confirm the FeB-ss-SiO₂ NPs (encapsulation with SiO2 outlayer containing -S-S- bonds) demonstrates the enhanced ferroptosis. The tumor-bearing mice models shows that FeB-ss-SiO₂ NPs exhibited superior biocompatibility and tumor inhibition effect (inhibition rate of 73%), which improve the overall survival rate for 30 days post-treatment. This study will provide an innovative way to design therapeutic nanoagents for cancer treatments.

Sirtuins as Key Regulators in Pancreatic Cancer: Insights into Signaling Mechanisms and Therapeutic Implications.

Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by rapid progression, pronounced chemoresistance, and a complex network of genetic and epigenetic dysregulation. Within this challenging context, sirtuins, NAD+-dependent deacetylases, have emerged as pivotal modulators of key cellular processes that drive pancreatic cancer progression. Each sirtuin contributes uniquely to PDAC pathogenesis. SIRT1 influences apoptosis and chemoresistance through hypoxia, enhancing glycolytic metabolism and HIF-1α signaling, which sustain tumor survival against drugs like gemcitabine. SIRT2, conversely, disrupts cancer cell proliferation by inhibiting eIF5A, while SIRT3 exerts tumor-suppressive effects by regulating mitochondrial ROS and glycolysis. SIRT4 inhibits aerobic glycolysis, and its therapeutic upregulation has shown promise in curbing PDAC progression. Furthermore, SIRT5 modulates glutamine and glutathione metabolism, offering an avenue to disrupt PDAC's metabolic dependencies. SIRT6 and SIRT7, through their roles in angiogenesis, EMT, and metastasis, represent additional targets, with modulators of SIRT6, such as JYQ-42, showing potential to reduce tumor invasiveness. This review aims to provide a comprehensive exploration of the emerging roles of sirtuins, a family of NAD+-dependent enzymes, as critical regulators within the oncogenic landscape of pancreatic cancer. This review meticulously explores the nuanced involvement of sirtuins in pancreatic cancer, elucidating their contributions to tumorigenesis and suppression through mechanisms such as metabolic reprogramming, the maintenance of genomic integrity and epigenetic modulation. Furthermore, it emphasizes the urgent need for the development of targeted therapeutic interventions aimed at precisely modulating sirtuin activity, thereby enhancing therapeutic efficacy and optimizing patient outcomes in the context of pancreatic malignancies.

Butyrate-producing Faecalibacterium prausnitzii suppresses natural killer/T-cell lymphoma by dampening the JAK-STAT pathway

BackgroundNatural killer/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with a dismal prognosis, and gaps remain in understanding the determinants influencing disease outcomes.ObjectiveTo characterise the gut microbiota feature and identify...

Suppressing GDF15 enhances the chemotherapeutic effect of 5 FU on MSI-H CRC by regulating the ferroptosis pathway SLC7A11/GSH/GPX4

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor beta (TGF-β) superfamily and is related to metabolism, injury, and aging. GDF15 has both tumor-promoting and tumor-suppressing effects. However, its role in colorectal cancer (CRC) with high microsatellite instability (MSI-H) must be further clarified. In our study, we found that GDF15 is generally elevated in pancarcinoma, particularly in colorectal cancer, and serves as an early indicator of the development of colorectal cancer. IHC and WB confirmed that GDF15 was elevated in MSI-H CRC clinical tissues and MSI-H CRC cell lines (HCT-116 and LoVo). Suppressing GDF15 by siRNA resulted in a substantial decrease in cell viability and proliferation. Furthermore, suppressing GDF15 can increase the sensitivity of MSI-H CRC cells to 5-fluorouracil (5-FU), which decreases cell viability and increases the apoptosis rate. In vivo experiments also demonstrated that mouse xenografts with suppressed GDF15 expression were more susceptible to 5-FU chemotherapy. We examined alterations in mitochondria via electron microscopy and changes in the mitochondrial membrane potential, ferroptosis-related signals (MDA, Fe2+), and SLC7A11/GSH/GPX4 protein pathway. Our research indicates that inhibiting GDF15 affects ferroptosis-related pathways, leading to ferroptosis and improving the MSI-H CRC response to 5-FU therapy. As a result, GDF15 could be a promising target for diagnosing and treating MSI-H CRC, potentially enhancing the overall effectiveness of therapy for patients with MSI-H CRC.

BEX4 inhibits the progression of clear cell renal cell carcinoma by stabilizing SH2D4A, which is achieved by blocking SIRT2 activity.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies. Recently, the role of brain-expressed X-linked 4 (BEX4) in cancer progression has received increasing attention. This study aimed to investigate the function of BEX4 in ccRCC and to reveal the underlying mechanisms. We first confirmed that BEX4 was significantly downregulated in ccRCC by bioinformatics analysis and that patients with low BEX4 expression tended to have prolonged overall survival time. Subsequently, we confirmed that BEX4 inhibited ccRCC cell proliferation in vitro and tumorigenesis in vivo through a series of cell function assays and the establishment of a nude mouse xenograft model, respectively. Mechanistically, we found that BEX4 positively regulates the expression of Src homology 2 domain-containing 4A (SH2D4A), an inhibitor of the NOTCH pathway, which further promoted the tumor-suppressive effects of BEX4. In addition, our study confirmed that the promoting effect of BEX4 on SH2D4A was achieved by inhibiting the deacetylase sirtuin 2 (SIRT2) activity. On this basis, we found that there was a competition between acetylation and ubiquitination modifications at the K69 site of SH2DA4 and that BEX4-induced upregulation of acetylation at the k69 site stabilizes SH2D4A protein expression by inhibiting ubiquitination at the same site. In addition, dual-luciferase assays showed that the transcriptional activity of BEX4 was positively regulated by activation transcription factor 3 (ATF3). Our study suggests that BEX4 plays a role in inhibiting tumor progression in ccRCC and maybe a new diagnostic and therapeutic target for ccRCC patients.

AKR1C3 mediates gastric cancer cell invasion and metastasis via the AKT and JNK/p-NF-κB signaling pathways

Gastric cancer (GC) is globally recognized as the fifth most common cancer and the third leading cause of cancer-related mortality. Early metastasis in GC significantly contributes to its high mortality and unfavorable prognosis. However, the underlying mechanisms of this phenomenon remain largely unexplored. Among the various factors involved, AKR1C3 has emerged as a crucial component in the pathways of tumorigenesis and metastasis across multiple cancer types. Yet, the precise significance of AKR1C3 in GC patients’ prognosis and its role in GC progression remain elusive. This study illuminated the significant downregulation of AKR1C3 in GC tissues, linking it to an aggressive phenotype and poor prognosis. Interestingly, while AKR1C3 overexpression did not affect the proliferation of GC cells, it significantly inhibited their ability to invade and metastasize. The underlying mechanism appears to involve AKR1C3’s inhibition of the p-JNK pathway, which leads to reduced phosphorylation of IKKα/β and IKBα, lowering p-NF-κB levels and hindering its movement into the nucleus, thereby stifling the epithelial-mesenchymal transition (EMT) process in GC cells. These insights reveal AKR1C3’s tumor-suppressive effects in GC and suggest its potential as a diagnostic and prognostic biomarker, offering new avenues for targeted therapies in gastric cancer management.

MiR-198 targets TOPORS: implications for oral squamous cell carcinoma pathogenesis.

miRNAs play a critical role in the progression of various diseases, including oral squamous cell carcinoma (OSCC), which represents a major health concern and is one of the leading causes for new cancer cases worldwide. The miRNA dysregulation causes havoc and could be attributed to various factors, with epigenetic silencing of tumor suppressor genes being a major contributor to tumorigenesis. In this study, we have explored the tumor suppressive role of miR-198 in OSCC. The tumor suppressive effect of miR-198 is established using miRNA analysis in OSCC cell lines, patient samples and xenograft nude mice model. The relationship between the miR-198 and TOPORS is explored using bioinformatics analyses, qRT-PCR, dual-luciferase reporter assay, Western blotting and cancer hall marks assays. The hypermethylation of the MIR198 promoter is confirmed using bisulfite sequencing PCR. We have found miR-198 to be upregulated in OSCC cells treated with 5-Azacytidine, a known DNA methyltransferase inhibitor. Upregulation of miR-198 in 5-Azacytidine treated OSCC cells appears to be due to methylation of the MIR198 promoter. Using bioinformatics analysis and dual-luciferase reporter assay, we have identified TOPORS (TOP1 binding arginine/serine rich protein, E3 ubiquitin ligase) as a novel gene target for miR-198. miR-198-mediated repression of TOPORS decreases cell proliferation and anchorage-independent growth and enhances apoptosis of OSCC cells, which is dependent on the presence of the 3'UTR in TOPORS. An inverse correlation between the expression levels of miR-198 and TOPORS is observed in OSCC patient samples, highlighting the biological relevance of their interaction. Delivery of a synthetic miR-198 mimic to OSCC cells results in a significant decrease in xenograft size in nude mice, potentiating its use in therapeutics. These results suggest that miR-198 is epigenetically silenced in OSCC, which promotes tumor growth, in part, by upregulating the levels of TOPORS.

Inhibition of PSF activity overcomes resistance to treatment in cancers harboring mutant p53.

Mutations in the TP53 tumor suppressor genes are prevalent in aggressive cancers. Pharmacological reactivation of dysfunctional p53 due to mutations is a promising strategy for treating such cancers. Recently, a multifunctional proline- and glutamine-rich protein, PTB-associated splicing factor (PSF), was identified as a key driver of aggressive cancers. PSF promotes the expression of numerous oncogenes by modulating epigenetic and splicing mechanisms. We previously screened a small-molecule library and discovered compound No.10-3 as a potent PSF inhibitor. Here, we report the discovery of a No.10-3 analog, C-30, as a potent PSF inhibitor. Compared to No.10-3, C-30 treatment specifically suppressed the growth and induced apoptosis of mutant p53-bearing and therapy-resistant cancer cells. Interestingly, C-30 activated a set of p53-regulated genes in therapy-resistant cancer cells. A comprehensive analysis of PSF and p53 binding regions demonstrated a higher level of PSF-binding potential in mutant p53-expressing cancer cells around genomic regions identified as p53-binding peaks in p53-wild type cancer cells. Treatment of mutant p53-expressing cancer cells with C-30 decreases PSF binding around these sites, leading to activated histone acetylation. We further demonstrated that C-30 impaired tumor growth and increased the expression of p53-target genes in vivo. These results suggested that C-30 produces tumor-suppressive effects similar to the functional reactivation of p53, providing a rationale for the inhibition of PSF activity as a promising therapy against treatment-resistant cancer.

GNAO1: A Novel Tumor Suppressor Gene in Colorectal Cancer Pathogenesis.

This study examined the role of GNAO1 as a potential tumor suppressor gene in colorectal cancer (CRC). RNA-seq data analysis revealed a significant GNAO1 down-regulation in colon cancer tissues compared to normal colon tissues. GNAO1 over-expression in CRC cell lines inhibited cell proliferation, migration, and tumor formation both in vitro and in vivo. This study suggests that GNAO1 exerts its tumor-suppressive effects by inhibiting the mTOR/S6K signaling pathway. The observed correlation between GNAO1 expression and cancer progression highlights its potential as a prognostic marker and therapeutic target in CRC. This study provides a foundation for further exploration of the molecular mechanisms by which GNAO1 influences CRC pathogenesis, with significant implications for its application in clinical settings.

Bifidobacterium animalis ssp. lactis BX-245-fermented milk alleviates tumor burden in mice with colorectal cancer.

Colorectal cancer (CRC) arises from the accumulation of abnormal mutations in colorectal cells during prolonged inflammation. This study aimed to investigate the potential of probiotic fermented milk containing the probiotic strain, Bifidobacterium animalis ssp. lactis BX-245 (BX-245), in alleviating tumor burden in CRC mice induced by azoxymethane and dextran sodium sulfate. The study monitored changes in tumor size and number, gut microbiota, metabolomics, and inflammation levels before and after the intervention. Our findings indicate that intragastric administration of BX245-fermented milk effectively modulated the intratumor microbiota, as well as the gut microbiota and its metabolism. We also observed a decreased relative abundance of intratumor Akkermansia in the CRC mice, while the intratumor Parabacteroides exhibited a significant positive correlation with tumor number and weight. Moreover, administering BX245-fermented milk significantly reduced gut barrier permeability, alleviated gut barrier damage, and increased serum interleukin-2 and interferon-γ levels compared with the ordinary fermented milk group. Collectively, our data suggest that administering probiotic fermented milk containing specific functional strains like BX245 could result in a reduction in tumor burden in CRC mice. Conversely, ordinary fermented milk did not show the same tumor-inhibiting effects. The current results are preliminary, and further confirmation is necessary to establish the causal relationship among probiotic milk, changes in gut microbiota, and disease alleviation.

Research Progress of Endoplasmic Reticulum Targeting Metal Complexes in Cancer Therapy.

The development of anticancer drugs that target different organelles has received extensive attention due to the characteristics of cancer recurrence, metastasis, and drug resistance. The endoplasmic reticulum (ER) is an important structure within the cell that is primarily responsible for protein synthesis, folding, modification, and transport and plays a crucial role in cell function and health. ER stress activation induces cancer cell apoptosis. New anticancer drugs with different anticancer mechanisms and selectivity can be designed because of redox activity, composition diversity, and metal complexes structure regulation. Over the past few decades, dozens of metal complexes have killed cancer cells through ER stress, showing powerful tumor-suppressive effects. This review summarizes the progress of research on anticancer metallic drugs that induce ER stress over the past few years, which is expected to bring more breakthroughs in the field of medicine and life science.

WTAP-Mediated m6A Modification of circSMOC1 Accelerates the Tumorigenesis of Non-Small Cell Lung Cancer by Regulating miR-612/CCL28 Axis.

Accumulating evidence reveals that deregulated N6-methyladenosine (m6A) RNA methylation and circular RNAs (circRNAs) are required for the tumorigenesis of non-small cell lung cancer (NSCLC). We aimed to uncover the underlying mechanisms by which WTAP-mediated m6A modification of circRNA contributes to NSCLC. The differentially-expressed circRNAs were identified by a circRNA profiling microarray. The association of circSMOC1 with clinicopathological features and prognosis in patients with NSCLC was estimated by fluorescence insitu hybridization. WTAP-mediated m6A modification of circRNA was validated by RNA immunoprecipitation (RIP) and methylated RIP (MeRIP) assays. The role of circSMOC1 in NSCLC cells was validated by invitro functional experiments and invivo tumorigenesis models. CircSMOC1-specific binding with miR-612 was verified by RIP, luciferase gene report and RT-qPCR assays. The effect of circSMOC1 and/or miR-612 on CCL28 expression was detected by RT-qPCR and Western blotting analysis. We found that the expression levels of circSMOC1 were elevated in NSCLC tissues and associated with TNM stage and poor survival in patients with NSCLC. Knockdown of circSMOC1 impaired the tumorigenesis of NSCLC invitro and invivo, whereas restored expression of circSMOC1 displayed the opposite effect. Furthermore, WTAP was upregulated in NSCLC and mediated m6A modification of circSMOC1 and circSMOC1 abolished WTAP knockdown-caused tumour-suppressive effects. Then, circSMOC1 acted as a sponge of miR-612 to upregulate CCL28 and miR-612 inhibitors abrogated circSMOC1 knockdown-caused anti-proliferation effects and CCL28 downregulation in NSCLC cells. Knockdown of CCL28 inhibited cell proliferation and invasion and counteracted miR-612 inhibitor-caused tumour-promoting effects. Our findings unveil that WTAP-mediated m6A modification of circSMOC1 facilitates the tumorigenesis of NSCLC by regulating the miR-612/CCL28 axis.

Synergistic effects of doxorubicin PLGA nanoparticles and simvastatin loaded in silk films for local treatment of breast cancer

An encouraging strategy to address challenges in breast cancer treatment is local drug delivery, targeting the primary tumor site to minimize side effects and drug resistance. Combination therapy, which uses multiple drugs, is effective in reducing drug doses and preventing cancer recurrence. In this study, a pH-responsive silk film containing doxorubicin loaded PLGA nanoparticles and simvastatin (SV/DOX PLGA/SF) to prevent local-regional recurrence, was developed. The DOX PLGA nanoparticles were synthesized in a microfluidic reactor by adjusting the flow rate and polymer concentrations. After optimization, these nanoparticles exhibited uniform size and spherical morphology (168 nm and PDI: 0.096) using concentrations of 0.5 % PLGA and 1 % PVA, and a flow rate of 1 mL/h. The degradation of SF by crosslinking for 7.5 min using methanol was found to occur over approximately 75 days. The release of DOX from DOX PLGA/SF was pH-dependent, with cumulative release on day 11 at pH 5.5 being 74.23 % and at pH 7.4 being 58.91 %. MTT results revealed a synergistic effect of SV and DOX, particularly notable at concentrations of 35 μM SV and 4 μM DOX after 24 h. SV/DOX PLGA/SF films demonstrated the highest tumor suppression effect and the lowest tumor recurrence in female Balb/c mice, with only around 52 ± 10.3 % of the initial tumor. Additionally, histopathological analysis using H&E staining indicated that SF-based localized treatments significantly reduced the mitotic index.

Exon 1 methylation status of CDH13 is associated with decreased overall survival and distant metastasis in patients with postoperative colorectal cancer

BackgroundCadherin 13 (CDH13) is a member of the cadherin superfamily that exerts tumor-suppressive effects on cancers derived from epithelial cells. Although hypermethylation of CDH13 promoter has been reported in various cancers, its prognostic value for colorectal cancer (CRC) is still controversial. The methylation alterations of CDH13 within exon 1 have not yet been investigated.MethodsA total of 49 CRC patients were recruited for the prospective study. The methylation status of CpG sites was quantified by Bisulfite Amplicon Sequencing (BSAS) in malignant tissues and adjacent normal tissues. The primary endpoint of the study was overall survival (OS) after surgery. The relationship between methylation level with pathological stage and OS was also evaluated.ResultsCompared with adjacent normal tissues, the overall average methylation level within exon 1 was significantly increased in tumor tissues (p < 0.001). The association study showed that the hypermethylation status of the CpG1 site was non-significantly associated with the presence of distant metastasis (p = 0.032). Moreover, the hypermethylation of two CpG sites, including CpG1 (p = 0.003) and CpG5 (p = 0.032), was associated with worse OS in CRC. Co-hypermethylation of CpG1 and CpG5 sites was significantly associated with a worse clinical outcome (HR: 4.43 [95% CI 1.27–15.46]; p = 0.019) in multivariate Cox regression analysis.ConclusionThe methylation level of CDH13 exon 1 in CRC tissue was significantly higher than in adjacent normal tissues. Hypermethylation at the CpG1 site suggests a risk of distant metastasis in CRC. The hypermethylation of the CpG1 site and CpG5 site, including the co-hypermethylation of these two sites, may serve as a valuable prognostic biomarker.

Structure-Activity Relationship Study of Majusculamide D: Overcoming Metabolic Instability and Severe Toxicity with a Fluoro Analogue.

Majusculamide D, isolated from the marine cyanobacterium Moorea producens, is an anticancer lipopentapeptide consisting of fatty acid, tripeptide, and pyrrolyl proline moieties. In this work, by utilizing a convergent synthetic approach, late-stage modification, and bioisostere strategy, 26 majusculamide D analogues were synthesized, and two (1i and 1j) demonstrated IC50 values < 1 nM against PANC-1 cancer cells. The results summarized a preliminary structure-activity relationship mainly at the C23, C4, C34, and C10 sites. A series of in vitro assays, including wound healing, transwell, clone formation, EdU, and western blot, confirmed that majusculamide D inhibited the migration, invasion, and proliferation of pancreatic cancer cells. The optimized fluorinated analogue 1n demonstrated a notable enhancement in stability during the mouse plasma assay (>50% left after 24 h), exhibited tumor-suppressive effects (51.5% at a dosage of 5 mg/kg), and successfully mitigated the severe toxicity (no mouse dead) observed in the group treated with majusculamide D (3 mice dead) in a xenografted mouse model.