Anti-Cancer Drugs最新文献

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with unmet needs for early diagnostic biomarkers and therapeutic targets. Recent studies highlight the role of histone lactylation (H3K18la) in modulating gene expression and tumor progression. Its specific mechanisms in CRC, however, remain poorly understood. This study analyzed 60 CRC patients to evaluate H3K18la levels in tumor and adjacent nontumor tissues via Western blot and correlated them with clinical parameters. CRC cell lines were treated with sodium lactate (Nala) to investigate H3K18la's regulatory effects on tumor necrosis factor (TNF) transcription. Mechanistic insights were derived from RNA sequencing, chromatin immunoprecipitation (ChIP) assays, luciferase reporter assays, and RT-qPCR. Diagnostic potential was assessed using receiver operating characteristic curve analysis. H3K18la levels were significantly elevated in CRC tissues compared with adjacent tissues and exhibited high diagnostic accuracy. High H3K18la expression correlated with larger tumor size and advanced american joint committee on cancer (AJCC) stages. Furthermore, H3K18la levels positively correlated with serum carcinoembryonic antigen and carbohydrate antigen 19-9. Nala treatment enhanced H3K18la enrichment at the TNF promoter, upregulating TNF transcription in CRC cells. Mechanistically, H3K18la directly activated TNF promoter activity, as demonstrated by luciferase reporter assays and ChIP analysis. In conclusion, H3K18la serves as a promising diagnostic biomarker for CRC, with strong correlations to tumor progression. Its oncogenic role is mediated, at least partially, through transcriptional activation of TNF. These findings position H3K18la as a novel therapeutic target for CRC and underscore its potential for early detection and personalized treatment strategies.

Desmoid tumors, known as aggressive fibromatosis, are derived from connective tissues, and local invasion is usually observed. Despite intensive efforts have been performed to investigate the novel anticancer agents in desmoid tumors, effective clinical management for treating desmoid tumors has not been developed yet. Additionally, the molecular mechanisms involved in the tumorigenesis of desmoid tumors have not been elucidated. In this study, given the frequent mutations of Wnt components and loss of function mutations in Trp53 in desmoid tumors, we developed the mouse models harboring Apc mutation with/without Trp53 knockout , Apc1638N/+ , and Apc1638N/+/Trp53-/- , respectively. We then established two primary cells derived from desmoid tumors in Apc1638N/+ and Apc1638N/+/Trp53-/- . Next, we have screened 3120 chemicals from a Food and Drug Administration-approved chemical library and identified halofuginone hydrobromide (HH), a collagen I-targeting compound, as exhibiting the most significant growth inhibition effects on Apc1638N/+ and Apc1638N/+/Trp53-/- desmoid tumor cells. Notably, HH also showed dramatic anticancer effects on colorectal cancer cells and mouse tumor organoids derived from intestinal tumors ( Apc1638N/+ ). Taken together, targeting collagen I is an effective therapeutic strategy for treating desmoid tumors and colorectal cancer patients.

Gastric cancer remains a major global health challenge, and its early diagnosis and prognosis prediction pose significant challenges to the current clinical treatment of gastric cancer. Finding gastric cancer biomarkers is essential to comprehending its pathophysiology and creating novel targeted treatments. Following the acquisition and processing of the gastric cancer sample, the single-cell RNA sequencing data, monocyte subpopulation characterization, and cell type identification were performed. Key gene modules linked to gastric-cancer-related monocytes were identified using high-dimensional weighted gene co-expression network analysis. Machine-learning diagnostic models were created utilizing the discovered gastric-cancer-related monocyte-related genes (GCRMORGs). A prognostic model was developed with the uridine phosphatase 1 ( UPP1 )-related risk scores and verified in separate cohorts, and multiple immunological analyses were performed. Finally, using various experimental assays, we thoroughly investigated the function of the UPP1 gene in gastric cancer. Gastric cancer samples showed a distinct immune milieu topography with an abundance of monocytes. Eventually, 32 GCRMORGs were identified. Diagnostic models demonstrated a high degree of efficacy in differentiating between patients with gastric cancer and the control group. The prognostic model showed significant predictive value for gastric cancer patients' survival. At the same time, we have confirmed from experimental perspectives that a poor prognosis for patients is indicated by a high expression of UPP1 in gastric cancer tissue. Important monocyte subpopulations associated with gastric cancer samples were detected in our investigation. The prognosis of patients with gastric cancer can be predicted using a predictive model based on 32 GCRMORGs. In addition, focusing on UPP1 in gastric cancer may yield novel therapeutic targets and approaches.

To investigate the role and underlying mechanism of α-linolenic acid (ALA) in ovarian cancer (OC), particularly its relationship with pyroptosis and the GPR120/caspase-1/Gasdermin D (GSDMD) pathway. Human OC cell lines (SKOV3, A2780), THP-1 monocytes, and SKOV3 subcutaneous xenograft models in nude mice were employed. Key assays included cell counting kit-8 (CCK-8) for cell viability, lactate dehydrogenase release for membrane damage detection, ELISA for Interleukin-1β (IL-1β) and IL-18 measurement, Western blot and quantitative polymerase chain reaction (qPCR) for analyzing pyroptosis-related molecules, molecular docking for ALA-GPR120 binding, and flow cytometry. Mice were administered ALA at a dose of 50 mg/kg by intraperitoneal injection, twice weekly for 4 weeks, or saline. ALA induced pyroptosis in OC cells both in vitro and in vivo, accompanied by increased membrane damage, elevated levels of IL-1β and IL-18, and activation of pyroptosis-related molecules. It targeted and inhibited GPR120 to activate the caspase-1/GSDMD pathway, with GSDMD identified as a critical effector. ALA also promoted M1 macrophage polarization and inhibited OC cell activity. In vivo, ALA reduced tumor size, upregulated pyroptosis markers, downregulated GPR120, and caused no significant toxicity. ALA induces OC cell pyroptosis and modulates the tumor microenvironment via the GPR120/caspase-1/GSDMD pathway, safely inhibiting OC growth. This reveals a novel mechanism, supporting ALA as a potential therapeutic candidate for OC, though further research into downstream regulation is required.

Gastric cancer (GC) poses significant therapeutic challenges due to frequent late-stage diagnosis and limited treatment efficacy. Although Apatinib demonstrates clinical benefits in GC, acquired resistance remains problematic. Ferroptosis induction represents a promising strategy to overcome such resistance. Integrated computational target prediction (SwissTargetPrediction) and ferroptosis suppressor gene screening (FerrDb) identified carbonic anhydrase IX (CA9) as Apatinib's putative target. Functional validation employed EdU, Transwell, sphere-formation, and flow cytometry assays. Ferroptosis markers [Fe²⁺, reactive oxygen species (ROS), ACSL4, and GPX4] were quantified via specific kits and western blotting. Histone deacetylase 1 (HDAC1)/hypoxia inducible factor 1α (HIF1α)/CA9 axis regulation was assessed through overexpression, siRNA knockdown, and immunoprecipitation. Apatinib significantly suppressed GC cell proliferation, migration, and stemness while promoting apoptosis. It induced ferroptosis via Fe²⁺/ROS accumulation and abnormal ACSL4/GPX4 expression. Mechanistically, Apatinib downregulated HDAC1, triggering HIF1α ubiquitination and subsequent CA9 suppression. HDAC1 overexpression reversed Apatinib-induced ferroptosis and antitumor effects, whereas HIF1α knockdown abrogated this rescue. This study elucidates a novel HDAC1/HIF1α/CA9 axis through which Apatinib induces ferroptosis. Targeting this pathway offers translational potential for overcoming Apatinib resistance in GC therapy.

This study aimed to explore the clinical significance and potential mechanisms of the transforming growth factor- β1 (TGF-β1)/small mother against decapentaplegic (SMAD) and nuclear factor kappa B (NF-κB) pathways in colorectal cancer (CRC). Transcriptomic and clinical data of CRC patients were retrieved from TCGA and GEO databases, analyzed via TCGAbiolinks, GEPIA 2, KEGG, and GO. A total of 275 colon cancer and 92 rectal cancer samples were included. Results showed TβR2 and SMAD2 expression was significantly associated with CRC pathological stage ( P  < 0.05), while low TGF-β1, TβR1, and TβR2 expression correlated with longer disease-free survival (DFS, P  < 0.05). Pathway component correlations differed between normal and cancerous tissues; high co-expression of NF-κB1 and SMAD2 linked to longer DFS in rectal cancer ( P  < 0.05). Signal transducer and activator of transcription 3 (STAT3) strongly correlated with NF-κB1, SMAD2/4 (R = 0.7, 0.63, 0.65; P  < 0.001), and combinations of NF-κB1 with SMAD2/SMAD4 showed strong correlations with STAT3 (R = 0.73; P  < 0.001). NF-κB1 combined with SMAD2 has prognostic value for rectal cancer, and STAT3 may be a common upstream transcription factor regulating both pathways.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic drivers in human cancer and are associated with poor prognosis, limited therapeutic options, and frequent resistance to standard treatments. The approval of the first direct KRAS G12C inhibitors demonstrated that mutant KRAS can be targeted clinically, but their efficacy is restricted to a narrow allelic subset and is limited by adaptive resistance. This review summarizes recent advances in KRAS-targeted drug development beyond G12C and outlines emerging strategies designed to improve therapeutic outcomes. A comprehensive literature review was conducted using preclinical and clinical data from studies investigating KRAS inhibitors, rat sarcoma (RAS) pathway modulators, and rational drug combinations. Particular attention was given to allele-specific agents, pan-RAS inhibitors, feedback signaling mechanisms, and resistance biology. Next-generation KRAS inhibitors targeting non-G12C alleles, including KRAS G12D selective agents, have demonstrated potent preclinical activity but remain susceptible to feedback mitogen-activated protein kinase (MAPK) reactivation. Pan-RAS inhibitors that bind the active RAS-GTP state show activity across multiple alleles and tumor types, although toxicity and therapeutic window remain key concerns. Indirect strategies targeting SHP2, SOS1, and downstream MAPK components enhance pathway suppression and delay resistance, especially in combination with direct KRAS inhibitors. Resistance mechanisms encompass secondary KRAS mutations, bypass signaling through alternative RAS isoforms, and activation of parallel pathways. Comutations such as STK11 or KEAP1 further influence therapeutic response and immune contexture. KRAS-directed therapy is rapidly expanding beyond G12C, with allele-specific inhibitors, pan-RAS approaches, and rational combinations offering new opportunities for broader clinical benefit. Ongoing challenges include toxicity management, resistance evolution, and the development of predictive biomarkers to guide therapy selection.

Many previous studies have investigated cetuximab and panitumumab's efficacy, safety, and side effects. Only a few studies have evaluated the relationship between toxicity and survival. Therefore, we conducted this study to examine the relationship between the side effects of anti-EGFR agents and survival in metastatic colorectal cancer patients. Our study is a single-center retrospective analysis of the medical records of 100 metastatic colorectal cancer patients between September 2014 and September 2023. Overall survival (OS) was found to be statistically significantly longer in patients who developed skin toxicity during anti-EGFR treatment (26.0 vs. 70.0 months) ( P  < 0.001). Similarly, OS was significantly better in patients with hypomagnesemia ( P  < 0.001) and constipation ( P  < 0.001) side effects. In contrast, OS was significantly worse in patients with lung toxicity ( P  = 0.016). Ocular side effects during anti-EGFR treatment did not affect OS statistically significantly ( P  = 0.268). The median PFS of patients with skin toxicity with anti-EGFR agents and hypomagnesemia in first-line treatment was 22.0 months (19.4-24.5) and 21.0 months (18.2-23.8), respectively ( P  = 0.002, P  = 0.022). In the second line, the median PFS of patients with skin toxicity and patients with hypomagnesemia who received anti-EGFR therapy was 19.0 months (6.2-31.8) and 17.0 months (8.4-25.6), respectively ( P  = 0.013, P  = 0.037). In our study, it was found that skin toxicity and hypomagnesemia positively affected both OS and PFS. OS was longer in patients with constipation, and OS was shorter in patients with lung toxicity. We suggest that survival might be predicted by monitoring side effects of these therapeutics; therefore, studies with larger cohorts are required.

Bortezomib resistance in multiple myeloma (MM) is a significant clinical challenge that limits the long-term effectiveness. Currently, there is a lack of reliable biomarkers to predict bortezomib resistance. Previous studies reported that several proteins regulate bortezomib resistance through targeting ubiquitin-proteasome pathways, including heat shock protein family A member 9 (HSPA9), dickkopf Wnt signaling pathway inhibitor 1 (DKK1), proteasome 26S subunit non-ATPase 14 (PSMD14), and tripartite motif containing 21 (TRIM21). In our study, we aimed to analyze the expression of these proteins in MM patients and evaluate their potential as biomarkers for bortezomib resistance. Our study enrolled 46 newly diagnosed MM patients (38 bortezomib-sensitive and eight bortezomib-resistant patients) and 52 healthy controls, and serum samples were collected from the patients before initial treatments. The levels of HSPA9, DKK1, PSMD14, and TRIM21 proteins in serum samples were measured using ELISA. The diagnostic power of HSPA9 protein for bortezomib resistance was evaluated through receiver operating characteristic curves combined with the area under curve (AUC). The correlation between HSPA9 protein and clinicopathological features was examined using the chi-square test, and Kaplan-Meier method and Cox regression analysis were applied to assess prognostic value. Compared with healthy controls, increased HSPA9 and DKK1, but decreased TRIM21 protein expression, were observed in serum samples from MM patients. There was no statistical difference in PSMD14 protein expression between the two groups. Notably, compared with bortezomib-sensitive patients, only HSPA9 protein was found to be upregulated in bortezomib-resistant patients, whereas no differences were found in the other proteins. Furthermore, the AUC of serum HSPA9 for differentiating MM patients from healthy controls was 0.906 [95% confidence interval (CI): 0.843-0.968]. And serum HSPA9 expression could effectively differentiate bortezomib-resistant MM patients from bortezomib-sensitive MM patients, with an AUC of 0.845 (95% CI: 0.734-0.957). In addition, elevated serum HSPA9 expression positively correlated with advanced International Staging System stage, increased β2-MG, abnormal immunoglobulin, and bortezomib resistance. Higher serum HSPA9 was linked to shorter overall survival rate and independently predicted poor prognosis. Our study demonstrated that elevated serum HSPA9 protein serves as a potential biomarker for bortezomib resistance and poor prognosis in MM patients.

Nasopharyngeal carcinoma (NPC) is highly prevalent in Southeast Asia and southern China, with most patients diagnosed at advanced stages. Although epidermal growth factor receptor (EGFR)-targeted therapies have shown clinical promise, their long-term efficacy is limited. This study explores the regulatory role of AdipoR1 in EGFR-targeted therapy response and evaluates adiponectin as a potential strategy to overcome treatment resistance. NPC cell lines (5-8F and CNE1) were treated with nimotuzumab for short (24 h) and long (72 h) durations. mRNA and protein expression of vascular endothelial growth factor (VEGF), AdipoR1/R2, and other pathway components were assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. Adiponectin was applied to explore its regulatory role in VEGF expression and EGFR signaling. Prolonged treatment of NPC cells with nimotuzumab inhibited EGFR downstream signaling [protein kinase B, mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase], reduced cell invasion and migration initially, but invasive capacity gradually recovered over time. VEGF expression remained unchanged at 24 h but significantly increased after 72 h, promoting angiogenesis in cocultured HUVECs. Long-term nimotuzumab exposure downregulated AdipoR1 expression, while adiponectin restored AdipoR1 and VEGF levels with decreased mTOR expression, not EGFR, indicating that the mTOR pathway may mediate this regulation. In addition, nimotuzumab elevated the expression of lipid metabolism-related genes, FABP4 and CD36, which was mitigated by A-PN cotreatment. Prolonged EGFR-targeted therapy in NPC upregulates VEGF via AdipoR1 downregulation, reducing treatment efficacy. Adiponectin restores AdipoR1, suppresses VEGF, and reverses this effect, possibly through mTOR inhibition, suggesting a potential strategy to improve long-term therapeutic outcomes.