Current Cancer Drug Targets - Online First

Euphorbia humifusa Willd (EH) is a traditional medicinal herb in China. However, the anti-prostate cancer active compounds of EH and their molecular mechanisms have yet to be elucidated.

The peaks of EH water extract in the fingerprinting were analysed using liquid chromatography coupled to quadrupole time of flight mass spectrometry. The cell viability of 22RV1 cells was determined via MTT. The active compounds and potential targets were screened in silico. The prostate cancer-associated targets were collected from the GeneCards database. The herb-compound-target-disease (H-C-T-D) and PPI networks were constructed to predict key targets. The molecular docking analysis of the active compounds with key targets was conducted using Autodock Vina 1.1.2. Western blot analysis was performed to evaluate the protein expression.

LC-MS results demonstrated that EH water extract is a rich source of phenolics and flavonoids. EH water extract inhibited the viability of 22RV1 cells in a time-and dose-dependent manner. Moreover, the in silico screening results identified 17 active compounds from EH with 518 prostate cancer-related key genes. Moreover, an H-C-T-D network analysis combined with the PPI network results effectively identified seven chemical compounds, oestrogen receptor 1, and androgen receptor (AR) to be highly related to prostate cancer. Furthermore, molecular docking results showed that 4′,5-dihydroxyflavone, ensaculin, luteolin, hypolaetin, quercetin, and kaempferol had a strong binding affinity with AR. Finally, Western blot results demonstrated that EH water extract, quercetin, kaempferol, and luteolin significantly down-regulated the AR protein expression in 22RV1 cells.

These results suggest that EH may provide a new promising therapeutic for prostate cancer treatment.

Hypoxia plays a crucial role in malignant tumor formation, primarily mediated by hypoxia-inducible factors (HIFs). Despite extensive research, the complexities and prognostic implications of the EGLN gene family (EGLN1, EGLN2, EGLN3) in cancers remain unclear.

Utilizing public databases (TCGA, GTEx, TARGET, GEO) and bioinformatics tools, a comprehensive analysis of EGLN genes across various cancer types was conducted. Gene expression, mutation data, stemness scores, and clinical information were integrated to evaluate the mutation landscape, expression levels, and prognostic values of EGLNs. Enrichment and pathway analyses explored EGLN-associated biological processes and functional networks. ssGSEA constructed EGLN scores for prognostic evaluation. Colocalization analysis combined eQTL and GWAS data to investigate genetic variations in cervical cancer. Immunohistochemistry validated EGLN expression in cervical cancer tissues.

EGLN genes showed differential expression across cancer types. EGLN1 overexpression was associated with worse survival in cervical squamous cell carcinoma (CESC), pancreatic adenocarcinoma (PAAD), and neuroblastoma (NB), while EGLN3 was linked to poor survival in CESC, lung adenocarcinoma (LUAD), and kidney cancers. EGLNs also demonstrated varied roles in modulating tumor immune activity and heterogeneity.

This study provides new insights into EGLN biology and identifies EGLN1 as a potential biomarker for cervical cancer.

Hepatocellular carcinoma (HCC) is a kind of fatal cancer with a variety of risk factors. However, a pan-etiology molecular characterization of HCC has not been explored.

The objective of this study is to explore etiology-specific features of HCC and improve our understanding of tumorigenesis, thereby revealing potential therapeutic targets.

RNA-seq, genetic alteration, copy number alteration, and clinicopathological data of The Cancer Genome Atlas -Liver Hepatocellular Carcinoma cohort were downloaded and explored. Immune-related features and single-cell and spatial transcriptomic data were adopted and analyzed.

Etiology-based analyses revealed that HCC with different etiologies showed different clinical features, including gender composition, ethnic composition, clinical stage distribution, and survival. In addition, distinct genetic alterations, copy number alterations, and tumor microenvironment were observed in HCC patients with different etiologies. Significantly enhanced expression of squalene epoxidase (SQLE) was observed in viral hepatitis-related HCC and was associated with poor tumor grade and overall survival. Correlation analysis revealed a negative relationship between SQLE expression and anti-tumor immunity. Single-cell and spatial transcriptomics demonstrated that SQLE contributed to reduced T cell and NK cell infiltration while increasing macrophage and monocyte infiltration.

The current study demonstrated that HCC has etiology-specific clinical features, genetic alteration, copy number alteration, and tumor microenvironment. Overexpression of SQLE in viral hepatitis-related HCC correlate with poor clinical outcome and may contribute to reduce T cell and NK cell infiltration while increased macrophage and monocyte infiltration, which lead to immunosuppressive microenvironment and can be an actionable target.

Cholangiocarcinoma (CC) is a rare, aggressive cancer of the bile ducts with limited treatment advancements over recent decades. The five-year survival rate for CC remains low, around 10%, and even lower for advanced cases.

This case report discusses a 46-year-old woman with metastatic CC who achieved remarkable progression-free survival with regorafenib, a multikinase inhibitor typically used in other cancers. After multiple lines of treatment, regorafenib was given as a 7th-line therapy. Despite initial intolerance requiring dose reduction, the patient achieved 22 months of progression-free survival (PFS) with stable disease and partial regression in some areas. Her response to regorafenib significantly exceeded typical outcomes in the literature, where PFS generally ranges from 3 to 4 months. This improvement may be attributed to an FGFR2 mutation identified via next-generation sequencing, which regorafenib may effectively target.

This case suggests that patients with FGFR2 mutations might benefit from regorafenib, warranting further studies to explore this associationAs can be applied as a promising target gene to develop drug resistance and remedial efficacy.

Gastric cancer is the third most lethal malignancy worldwide. While cisplatin has shown remarkable efficacy at a low cost, it is also associated with severe side effects. Exosomes play a key role in mediating the bystander effect of radiation and have the capacity to deliver apoptosis signals for targeted destruction of tumor cell. However, there remains a paucity of research on exosome-mediated bystander effects in the context of chemotherapeutic drugs.

This study aims to investigate the ability of cisplatin-induced exosomes to deliver apoptosis signals to gastric cancer cells, with the aim of mitigating the adverse effects associated with chemotherapy.

Differential ultracentrifugation was used to isolate apoptotic exosomes secreted by cisplatin-induced gastric cancer MKN-28 cells. Characterization and identification of these exosomes were performed by transmission electron microscopy, particle size analyzer, flow cytometry, and Western blotting. The transduction efficiency of the exosomes was confirmed through immunefluorescence. The effects of apoptotic exosomes on the proliferation, apoptosis, migration, cycle, senescence, and tumor formation of MKN-28 cells in vitro and in vivo were investigated by live cell workstation, flow cytometry, HE staining, and tumorigenicity assays.

Cisplatin-induced apoptotic exosomes, termed DDP-EXO, exhibited a significantly enhanced inhibitory effect on the proliferation of MKN-28 cells compared to gastric epithelial GES-1 cells. Moreover, DDP-EXO was able to deliver apoptotic signals to MKN-28 cells, leading to an increase in the apoptotic population in recipient cells, possibly through the involvement of Caspase-9. Furthermore, DDP-EXO showed limited impacts on cell migration, cell cycle, or cell senescence. In vivo, DDP-EXO effectively suppressed tumorigenesis in a subcutaneous tumor model without causing detectable pathological changes in main organs and blood samples, suggesting a favorable safety profile.

In summary, this study provides new perspectives on the potential application of exosomes as an innovative therapeutic approach for gastric cancer.

This study aimed to investigate the effect and mechanism of arctigenin (ARG) on the sensitization of dacarbazine (DTIC) via the regulation of mitophagy.

In vitro experiments were conducted to explore the effects of ARG on the biological behavior of melanoma cells, mitochondrial autophagy mediated by PINK1/Parkin, and the role of reactive oxygen species (ROS)-mitochondrial autophagy in the regulation of the biological behavior of melanoma cells by an ROS quenching agent, a mitochondrial autophagy inhibitor, and an activator. The effects of ARG and dacarbazine in nude mice were assessed.

CCK8 assays revealed that ARG inhibited the proliferation of the human melanoma cell lines A375 and SK-MEL-2. The observation of submicroscopic structures demonstrated mitochondrial damage. Flow cytometry further verified that ARG induced apoptosis. Western blot analysis revealed that the protein expression levels of cleaved caspase 3 and Bax increased, whereas that of Bcl-2 decreased. In addition, ARG increased ROS levels. LC3II/I, PINK1, and Parkin were increased. ARG-induced apoptosis was related to increased mitochondrial oxidative stress and promoted the occurrence of mitochondrial autophagy. After the addition of the autophagy inhibitor Mdivi-1 or the ROS quencher N-acetylcysteine (NAC), the antiproliferative effect of ARG was markedly attenuated. The expression levels of PINK1, Parkin, LC3II/I, cleaved caspase 3, and Bax were increased, whereas that of Bcl-2 was decreased. The formation of mitochondrial autophagosomes was observed by transmission electron microscopy. ARG inhibited the proliferation and induced the apoptosis of melanoma cells in vivo.

Autophagy-mediated cell apoptosis was activated through the PINK1/Parkin pathway by ARG, effectively inhibiting the proliferation of human melanoma cells.

Prosopis cineraria L. (PCL) is a herbal plant commonly used in Asia for the therapeutic intervention of different kinds of illnesses. Preclinical reports have revealed the beneficial effects of PCL against various types of life-threatening diseases, including cancer. However, studies targeting breast cancer (BCa) and bioactive for its mechanistic approach are limited or not available.

The current work utilized network pharmacology, built a network between plant compounds and BCa targets, and explored the effective phytocompounds of PCL and its possible mode of action. All phytoconstituents of PCL were segregated using the IMPPAT database, and thus, potential phytoconstituents were selected for this study. Phytocompounds and BCa target data were entered into Cytoscape software to compose the PCL network, and subsequently GO and pathway enrichment analysis were examined. Molecular docking and in vitro experiments were used to further validate the network pharmacology results.

We retrieved 24 phytocompounds from PCL and 301 potent BCa-associated targets for network construction, and obtained one main ingredient, luteolin of PCL. MMP9, GSK3Β, PARP1, CYP19A1, MMP2, ABCG2, ESR2, HMGCR, AR, and ABCB1 have been recognized as crucial targets of PCL in BCa treatment. Subsequent in vitro experiments showed that PCL and its final screened constituent, luteolin, inhibited the proliferation of MDA-MB-231 cells and reduced the expression level of MMP9 target genes.

Network analysis exhibited that PCL exerted a significant repressive impact on BCa by acting on tumor-associated signaling cascade, which would be helpful for future anticancer research of PCL against breast cancer.

Prior research has demonstrated that proteins play a significant role in the prognosis and treatments of various sarcomas, including Ewing sarcoma through the interplay of downstream signaling cascades. However, there is limited understanding about the strcucture conformation of EWSR1 and its structural implication in the prognosis of Ewsing Sarcoma by interaction with RNA molecules.

The primary goal of ongoing research is to determine how EWSR1 contributes to Ewing sarcoma.

The current study explores the complexity of EWSR1 structure and its conformational interactions with RNA in relation to Ewing sarcoma.

Here, we employed a comparative modeling approach to predict EWSR1 domains separately and assembled them into one structural unit using a DEMO server. Additionally, the RNA motifs interacting with EWSR1 were predicted, and the 3D model was built using RNAComposer. Protein-RNA docking and MD simulation studies were carried out to check the intermolecular interactions and stability behavior of docked EWSR1-RNA complexes.

The overall results explore the structural insights into EWSR1 and their interactions with RNA, which may play a momentous role in co- and post-transcriptional regulation to control gene expression.

Taken togather, our findings suggest that EWSR1 may be a useful therapeutic target for the diagnosis and management of Ewing sarcoma.

Historically, there has been a lack of focus on the mortality rates of individuals with both diabetes and Bladder Bancer (BC). Our study aimed to identify the risk factors associated with death from Diabetes Mellitus (DM) in BC patients.

Data was gathered from the SEER database on individuals who were diagnosed with BC between the years 2000 and 2017. Calculation of the Standardized Mortality Ratio (SMR) was performed to determine the mortality rate of DM in patients from BC. Potential risk factors for DM mortality were identified by a multivariate competing risk model. Hazard Ratios (HR), with 95% confidence intervals (95% CI) were used to indicate the degree of associated risk.

A total of 217,230 BC patients' data were collected from the SEER database for analysis. Among them, 98,880 patients passed away, and 1,783 patients encountered DM mortality. The overall SMR for DM mortality in BC patients was 3.32 (95% CI: 3.17-3.48). Results indicated that SMR increased with increasing years but decreased with increasing follow-up time. Multivariate competing risk analysis shows that BC patients with the following factors were at higher risk of developing DM mortality: advanced age, male, black, in situ tumor stage, early year of diagnosis, pathology type of transitional cell carcinoma, without chemotherapy or radiation therapy, and absence of spouse (including separated, divorced, widowed, and unmarried).

Individuals diagnosed with BC are at a considerably elevated risk of mortality from DM compared to the general population. It is of the utmost importance to identify high-risk groups and implement effective interventions for DM in order to enhance the survival rate among this patient population.

Quinoline derivatives, often incorporating other heterocyclic structures, have shown a wide range of therapeutic potential, especially in the treatment of cancer. These compounds have demonstrated significant anticancer activity against various cell lines, including HeLa (human cervical cancer) and MDA-MB-435 (melanoma), exhibiting strong inhibitory effects.

In this study, arylhydrazonopyrazole derivatives (3a-c) were employed in a series of multicomponent reactions to synthesize 3,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinoline and pyran derivatives. Pyrazolo[1,5-a]quinoline derivatives, due to their structural properties, are considered valuable scaffolds for the development of novel drugs targeting similar biological pathways, with the potential for improved therapeutic efficacy. This study aimed to demonstrate the use of simple arylhydrazonopyrazole derivatives in multicomponent reactions with cyclic ketones and aromatic aldehydes. The resulting compounds were then assessed for their cytotoxic and antiproliferative activities. Following these reactions, further heterocyclization processes were conducted, incorporating the quinoline moiety into the final structures. These findings underscore the potential of pyrazolo[1,5-a]quinoline derivatives as promising candidates for drug discovery, offering new avenues for targeting diseases with related molecular mechanisms.

The key starting compound in this study was 3,5-dimethyl-4-(2-phenylhydrazono)-4H-pyrazole, which has been utilized in numerous heterocyclization reactions. These reactions, involving various reagents, such as cyclic ketones and diketones in the presence of aromatic aldehydes, led to the formation of fused tetracyclic compounds. Arylhydrazonopyrazole derivatives (5a-c) were employed in multicomponent reactions to synthesize 3,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinoline and pyran derivatives. The reactions were carried out using both conventional catalysts and ionic liquid-immobilized catalysts. Notably, the use of ionic liquid-immobilized catalysts resulted in higher yields of the desired compounds.

In this study, new compounds were synthesized, characterized, and evaluated for their cytotoxicity against six cancer cell lines: A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460. Additionally, the cytotoxic effects of the synthesized compounds were assessed against hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cell lines. Morphological studies of selected compounds were also conducted to further understand their effects on the cancer cells. Moreover, the cytotoxicity of the selected compounds was tested against seventeen different cancer cell lines, categorized by disease type. Morphological analyses of these selected compounds were also performed to gain deeper insights into their potential as anticancer agents.

The inhibition assays of the tested compounds demonstrated significant activity against c-Met enzymatic activity, with IC50 values ranging from 0.25 to 10.30 nM. Additionally, potent inhibition was observed in the prostate PC-3 cell line, with IC50 values ranging from 0.19 to 8.62 µM. These promising results highlight the potential of these compounds and encourage further research to explore their therapeutic applications in the future.

Lenvatinib is an oral tyrosine kinase inhibitor that selectively inhibits receptors involved in tumor angiogenesis and tumor growth. It is an emerging first-line treatment agent for hepatocellular carcinoma (HCC). However, there is no intravenous administration of Lenvatinib.

This study aimed to construct nanocomposites that can efficiently support Lenvatinib and target liver cancer tissues and cells.

In this study, ferric oxide-viral-like mesoporous silica nanoparticles-folic acid (Fe3O4-vMSN-FA) nanocomposites loaded with Lenvatinib were constructed, and their anti-hepatocellular carcinoma effects were evaluated.

The hydrothermal method was used to synthesize ferric oxide (Fe3O4). Ferric oxide-viral-like mesoporous silica nanoparticles (Fe3O4-vMSN) were synthesized using a two-phase method. Then, Fe3O4-vMSN was modified with folic acid (Fe3O4-vMSN-FA) to better target tumor cells.

The experimental data showed that Fe3O4-vMSN-FA nanocomposites were successfully synthesized and could be loaded with Lenvatinib (Len@ Fe3O4-vMSN-FA). Fe3O4-vMSN-FA had good stability and biocompatibility, and it can release the loaded Lenvatinib faster in an acidic environment (pH 5.5). CCK8 assay and flow cytometry showed that HepG2 cells in the Len@ Fe3O4-vMSN group had the lowest cell viability and the highest apoptosis rate, confirming the anticancer properties of Len@ Fe3O4-vMSN-FA in vitro. In addition, transwell experiments showed that the migration and invasion ability of HepG2 cells in the Len@ Fe3O4-vMSN-FA group were significantly inhibited. In vivo fluorescence imaging in mice confirmed the enhanced tumor-targeting ability of Fe3O4-vMSN-FA. The tumor volume of the Len@ Fe3O4-vMSN-FA group was significantly reduced, and there was no significant effect on body weight. Moreover, serum liver function index (ALT and AST) and HE staining showed that Len@ Fe3O4-vMSN-FA did not cause obvious damage to organ tissue.

Len@ Fe3O4-vMSN-FA has a good anti-liver cancer effect. Fe3O4-vMSN-FA can be used as an alternative platform for drug delivery, providing more options for cancer therapy.

Nasopharyngeal cancer [NPC] is prevalent in Southeast Asia and North Africa, and is generally associated with limited treatment options and poor patient prognosis.

Ferroptosis is a recently observed cell death modality and has been shown to link to the efficacy of different anti-cancer treatments, thus offering opportunities for the development of novel therapies. This study aims to investigate the potentiating effects of COX-2 inhibitors on ferroptosis in nasopharyngeal cancer.

The inhibitory effects of COX-2 inhibitors celecoxib and rofecoxib on nasopharyngeal cancer cells were assessed with MTT, colony formation, sphere formation, Transwell, and wound healing assays. The status of COX-2 with celecoxib and rofecoxib treatment was investigated by Western blotting and immunofluorescence experiments. Ferroptosis was induced with the GPX4 inhibitor RSL3 with or without COX-2 inhibition and was monitored by fluorescence microscopy. Transcriptomic profiling was conducted with 5-8F cells treated with DMSO as control or celecoxib, and ferroptosis-related candidates were validated by RT-PCR analysis.

Celecoxib and rofecoxib effectively inhibited the growth and migration of nasopharyngeal cancer cells. Both inhibitors evidently sensitized nasopharyngeal cancer cells to ferroptosis induction by RSL3, with celecoxib outperforming rofecoxib. Celecoxib treatment resulted in significantly differentially expressed genes in 5-8F cells, among which CHAC1 was validated as a ferroptosis-related target.

The COX-2 inhibitor celecoxib effectively sensitized nasopharyngeal cancer cells to ferroptosis induction.

Gastrointestinal (GI) cancers represent some of the most common and lethal malignancies globally, underscoring the urgent need for improved diagnostic strategies. Traditional diagnostic methods, while effective to some degree, are often invasive and unsuitable for regular screenings.

This review article explores integrating machine learning (ML) with liquid biopsy techniques as a revolutionary approach to enhance the detection and monitoring of GI cancers. Liquid biopsies offer a non-invasive alternative for cancer detection through the analysis of circulating tumor DNA (ctDNA) and other biomarkers, which when combined with ML, can significantly improve diagnostic accuracy and patient outcomes.

We conducted a comprehensive review of recent advancements in liquid biopsy and ML, focusing on their synergistic potential in the early detection of GI cancers. The review addresses the application of next-generation sequencing and digital droplet PCR in enhancing the sensitivity and specificity of liquid biopsies.

Machine learning algorithms have demonstrated remarkable ability in navigating complex datasets and identifying diagnostically significant patterns in ctDNA and other circulating biomarkers. Innovations such as machine learning-enhanced “fragmentomics” and tomographic phase imaging flow cytometry illustrate significant strides in non-invasive cancer diagnostics, offering enhanced detection capabilities with high accuracy.

The integration of ML in liquid biopsy represents a transformative step in the early detection and personalized treatment of GI cancers. Future research should focus on overcoming current limitations, such as the heterogeneity of tumor-derived genetic materials and the standardization of liquid biopsy protocols, to fully realize the potential of this technology in clinical settings.

Data sourced from the Surveillance, Epidemiology, and End Results (SEER) database encompassing liver cancer diagnoses from 2000 to 2017 were utilized. The standardized mortality rate (SMR) was computed using general population reference data, and multivariate competing risk models were employed for analysis.

Analysis of 70,733 liver cancer patient records revealed 1,954 instances of CVM. The overall CVM SMR for liver cancer patients was 12.01 (95% CI: 11.48-12.55). Various demographic and clinical factors, including sex, race, age, year of diagnosis, pathological type, general stage, treatment modalities, and matrimonial status, emerged as liver cancer patients` independent predictors of CVM.

Liver cancer patients have a notably heightened susceptibility to cardiovascular mortality (CVM) in contrast to the general populace. It is imperative to promptly recognize high-risk subcategories and execute tailored cardiovascular interventions as crucial measures to bolster survival rates within this cohort of patients.

Ferroptosis, a regulated cell death initiated by Fe-dependent lipoperoxidation, is closely linked to the development of lung adenocarcinoma (LUAD). LncRNA human leukocyte antigen complex P5 (HCP5) has been confirmed as oncogenic in LUAD, but its function in ferroptosis is unknown.

Based on the previous bioinformatics mining of the ceRNA (competitive endogenous RNA) network HCP5/miR-17-5p/ Homeobox A7 (HOXA7) related to ferroptosis in LUAD, in this study, we characterized the cell-based experiments to validate the binding between the HCP5/miR-17-5p/HOXA7 axis and ferroptosis.

The HCP5/miR-17-5p/HOXA7 linkage was identified by a two-luciferase reporter. Cell Counting Kit-8 (CCK-8) and Transwell assay were employed for the detection of viability, invasion, and migration of A549 cells, respectively. ACSL4 and SLC7A11 were associated with ferroptosis, MMP 9, vimentin, and E-cadherin, which were associated with migration and invasion and were assessed by WB and qRT-PCR. Fe2+ and malondialdehyde (MDA) were analyzed using kits.

Over-expression of HCP5 enhances the growth, invasion, and migration of A549 cells by adjusting miR-17-5P to increase the expression of HOXA7. In addition, the knockdown of HCP5 elevated miR-17-5p, which inhibited HOXA7 expression and suppressed ferroptosis and EMT in A549 cells.

HCP5/miR-17-5p/HOXA7 can affect ferroptosis as well as the biological behavior of A549 cells.

PANoptosis, a novelty mechanism of cell death involving crosstalk between apoptosis, pyroptosis, and necroptosis, is strongly associated with tumor cell death and immunotherapy efficacy. However, its relevance in lung adenocarcinoma (LUAD) remains to be elucidated.

In this study, we acquired 18 PANoptosis-related differentially expressed gene (PRDEG) of LUAD. Based on these genes, LUAD samples were identified with different subtypes by unsupervised clustering. Next, we compared the differences between the subtypes, including clinical features, immune microenvironment, and potentially sensitive drugs. Furthermore, we used machine learning to identify hub prognostic PRDEGs, construct a risk score, and validate it on other external datasets. We incorporated the patient's clinical information and risk score into the proportional hazards model and lasso-cox models to find key prognostic features and constructed five prognostic models. The best model was identified via the area under the curve and validated on an external dataset.

LUAD patients were divided into two clusters named C1 and C2, respectively. The C2 cluster exhibited shorter survival time, more advanced tumor stage, higher suppressive immune cell scores, such as dendritic cells, and higher expression of inhibitory immune checkpoints, such as LAG3 and CD86. TIMP1, CAV1, and CD69 were recognized as key prognostic factors, and risk scores predicted survival with significant differences in the external validation set. Risk score and N-stage were identified as critical prognostic features. The Coxph model outperformed other machine learning clinical models. The 1-, 3-, and 5-year time-ROCs in the external validation set were 0.55, 0.59, and 0.60, respectively.

We demonstrated the potential of PANoptosis-based molecular clustering and prognostic features in predicting the survival of patients with LUAD as well as the tumor microenvironment.

Apatinib, a tyrosine-kinase inhibitor that targets the vascular endothelial growth factor receptor 2, contributes to the inhibition of angiogenesis. Vinorelbine, a semisynthetic vinca alkaloid, primarily inhibits metaphase mitosis of cancer cells through its interactions with tubulin. This study aimed to evaluate whether apatinib combined with vinorelbine was effective and safe for refractory human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients who failed taxanes and/or anthracycline and analyze the possible mechanism of drug resistance through metabolomic analysis.

Eligible patients were HER2-negative, inoperable, locally advanced, or metastatic breast cancer patients who progressed after at least one chemotherapy regimen in this present prospective phase II study. Patients took oral apatinib (250-500 mg/day) plus intravenous infusion of vinorelbine (25 mg/m² on day 1, day 8 at 3-week intervals). Objective response rate (ORR) was our primary endpoint, while disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity were our secondary endpoints. The exploratory purpose was to identify biomarkers or drug resistance mechanisms through metabolomics changes before and after the combination therapy.

Between September, 2019 and June, 2022, a total of 34 patients were included. ORR and DCR were 32.4% (11/34) and 85.3% (29/34), respectively. The median PFS was 5.0 months (95% CI, 3.766-6.234), while the median OS was 13.0 months (95% CI, 8.714-17.286). Side effects included hematologic toxicity, gastrointestinal reaction, and sinus tachycardia, which were mild to moderate. The mainly disturbed metabolic pathways were the cAMP signaling pathway, the alanine/aspartate/glutamate metabolism, the central carbon metabolism in cancer, the beta-alanine metabolism, the butanoate metabolism, and the glyoxylate and dicarboxylate metabolism, which may lead to the resistance of patients to this combination therapy.

Apatinib combined with vinorelbine is effective and safe in patients with locally advanced or metastatic refractory HER2-negative breast cancer. The findings of this study contribute to a better understanding of the metabolic effect of apatinib and vinorelbine therapy.

ChiCTR1900025659.

This study aimed to investigate the expression pattern of phosphatidylinositol 3-kinase class III (PIK3C3/vps34) in gastric cancer (GC) tissues and their juxtaposed normal counterparts and its correlation with the clinicopathological attributes and prognostic outlook of afflicted individuals.

Immunohistochemical (IHC) staining was used to ascertain the expression levels of PIK3C3/vps34 across 60 GC tissues juxtaposed with their normal counterparts. Statistical methodologies were used to scrutinize the correlation between PIK3C3/vps34 expression and clinicopathological features, along with prognostic implications for GC patients.

In GC tissues, the positive expression rate of PIK3C3/vps34 was 23.3% (14/60), which contrasted sharply with the markedly elevated rate of 66.7% (40/60) observed in adjacent tissues. The positive expression proportion of PIK3C3/vps34 within GC tissues exhibited a notable decrease than in adjacent tissues (P < 0.05). The expression of PIK3C3/vps34 inversely correlated with tumor size, degree of tissue differentiation, depth of tumor infiltration, and incidence of lymph node metastasis (P < 0.05), whereas no significant associations were found with patient sex, age, tumor location, TNM staging, or distant metastasis (P > 0.05). As the tumor diameter increases, the degree of tissue differentiation diminishes, tumor infiltration depth intensifies, lymph node metastasis emerges, the TNM stage progresses, and PIK3C3/vps34 expression level within GC tissues declines correspondingly. Kaplan-Meier survival analysis unveiled a prolonged survival duration among GC patients exhibiting heightened PIK3C3/vps34 expression than in their counterparts with diminished expression (HR=0.66, 95% CI: 0.55-0.80), demonstrating statistical significance (P < 0.05). Protein interaction analysis revealed noteworthy interactions involving PIK3C3 with Beclin 1, UVRAG, and ATG14.

PIK3C3/vps34 is downregulated in GC tissues, exerting a pivotal role in tumorigenesis, and is intimately linked with the prognostic trajectory of GC patients. It may serve as a significant biomarker for prognostic evaluation and a promising molecular therapeutic target for GC.

Cost-effective management of Urinary Bladder Cancer (UBC) is an unmet need.

Our study aims to demonstrate the efficacy of a drug repurposing strategy by using disulfiram (DSF) and copper gluconate (Cu) as an add-on treatment combination to traditional GC-based chemotherapy against N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced UBC mice (C57J) model.

Male C57BL/6J mice were given 0.05% BBN in drinking water ad libitum, and tumour formation was verified by histological and physical evaluation. Animals were subsequently divided into eight groups and received treatment with different drug combinations. Control animals received only vehicle (DMSO). At the end of the treatment schedule, the bladder tumour was excised and further used to check the expression (mRNA and protein) of ALDH1 isoenzymes using qRT-PCR, western blot, and IHC methods. Autophagy induction was assessed by quantifying the expression of LC3B and SQSTM1/p62 proteins through IHC. Biochemical analysis of superoxide dismutase (SOD), reduced glutathione (GSH), and lipid peroxidation levels in the freshly isolated tumours was performed to check the alterations in the antioxidant system caused by combination treatment.

We observed significant induction of an invasive form of bladder cancer in the mice after nineteen weeks of BBN exposure. The animals began exhibiting early indications of inflammatory alterations as early as the sixth week following BBN treatment. Furthermore, the wet bladder weight and overall tumour burden were significantly decreased (p< 0.0001) by DSF-Cu co-treatment in addition to the GC-based chemotherapy. Real-time PCR analysis revealed that treatment with disulfiram and copper gluconate significantly decreased (p<0.0001) the mRNA expression of ALDH1 isoenzymes. Comparing the triple drug combination group (GC+DSF-Cu) to the untreated mice, a significant rise in LC3B puncta (p<0.0001) and a decrease in P62/SQSTM1 (p=0.0002) were noted, indicating the induction of autophagy flux in the add-on group. When GC+DSF-Cu treated mice were compared to the untreated tumour group, a substantial decrease in ALDH1/2 protein expression was observed (p= 0.0029 in IHC and p<0.0001 in western blot). Lipid peroxidation was significantly higher (p<0.0001) in the triple drug combination group than in untreated mice. There was a simultaneous decrease in reduced glutathione (GSH) and enzyme superoxide dismutase (SOD) levels (p<0.0001), which strongly suggests the generation of reactive oxygen species and induction of ferroptotic cell death in the add-on therapy group. Additionally, in both IHC and western blot assays, ALDH1A3 expression was found to be significantly increased (p=0.0033, <0.0001 respectively) in GC+DSF-Cu treated mice relative to the untreated group, suggesting a potential connection between the ferroptosis pathway and ALDH1A3 overexpression.

It was found that disulfiram with copper treatment inhibits bladder tumour growth through ferroptosis-mediated ROS induction, which further activates the process of autophagy. Our results prove that DSF-Cu can be an effective add-on therapy along with the standard chemotherapy drugs for the treatment of UBC.