Anti-Cancer Drugs最新文献

Advanced hepatocellular carcinoma (HCC) with extensive metastases is associated with a poor prognosis, highlighting the need for individualized, multimodal treatment strategies. We present the case of a 54-year-old male with advanced HCC (cT3NxM1, Child-Pugh B) and spinal as well as bilateral pulmonary metastases who experienced disease progression after multiple lines of therapy. A dynamically adjusted, multidisciplinary regimen was implemented, incorporating transarterial chemoembolization (TACE), surgery, immunotherapy, and targeted therapy. The final regimen - combining nivolumab plus ipilimumab (O+Y) with TACE and lenvatinib - achieved a partial response in lung metastases, with a progression-free survival exceeding one year and overall survival of over 24 months. This case underscores the therapeutic potential of O+Y in later-line settings and demonstrates the clinical value of an integrated, personalized treatment paradigm for advanced HCC.

Dysregulated expression of mitochondrial creatine kinase 1B (CKMT1B), a member of the creatine kinase family, has been linked to tumor progression. However, its specific function in lung adenocarcinoma (LUAD) remains unclear. Bioinformatics analyses were performed to evaluate CKMT1B and its upstream transcription factor PITX2 in LUAD. CKMT1B and PITX2 expression levels were determined by quantitative PCR. The functional impact on cell stemness was subsequently evaluated using CCK-8, sphere formation assay, flow cytometry, and western blot. CKMT1B-mediated lipid accumulation was examined via BODIPY staining and measurements of triglyceride and glycerol concentration. The PITX2-CKMT1B interaction was validated through dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays, with the regulatory mechanism further substantiated by functional rescue experiments. CKMT1B was upregulated in LUAD and linked with poor prognosis. Its knockdown suppressed cell proliferation, sphere-forming capacity, and stemness-related protein expression (CD133, Bmi-1, SOX-2). Furthermore, CKMT1B overexpression facilitated lipid accumulation and stemness, effects that were reversible by the lipase inhibitor Orlistat. Mechanistically, PITX2 was identified as an upstream transcription factor of CKMT1B. PITX2 expression was positively correlated with CKMT1B, and high PITX2 expression predicted poor outcomes. In functional rescue experiments, PITX2 knockdown significantly reduced lipid accumulation and stemness, while these effects were partially restored by CKMT1B overexpression. PITX2 promotes lipid accumulation and enhances stemness in LUAD cells by transcriptionally activating CKMT1B, suggesting the PITX2/CKMT1B axis as a potential therapeutic target for LUAD treatment.

Neurotoxicity is one of the major complications in cancer patients following paclitaxel-containing regimens. Matricaria chamomilla L., isolated from the German chamomile, has anti-inflammatory and antioxidant features. In this study we evaluated the preventive impact of a chamomile oral formulation against paclitaxel-induced neurotoxicity in cancer patients. In this triple-blind clinical trial, cancer patients on paclitaxel were randomly allocated to chamomile oral solution (n = 40), or the placebo (n = 40) 5 ml three times a day for four courses of chemotherapy starting one day before the paclitaxel injection. At the end of each chemotherapy course, patients in both groups were evaluated and graded according to CTCAE (Common Terminology Criteria for Adverse Events). Also, anxiety and sleep disorder were evaluated at the beginning and end of the study based on Generalized Anxiety Disorder-7 and Pittsburgh Sleep Quality Index criteria, respectively. At the end of the four cycles of chemotherapy, there was no significant difference between the two groups in terms of the neuropathy CTCAE score. In terms of the various components of the sleep questionnaire, only the individual's overall description of sleep quality at the end of the study was significantly better in the treatment group (P = 0.026). Sleep quality was also significantly better (P = 0.027), and the chance of good sleep quality in the intervention group was 4.48 times higher. Regarding the anxiety score, despite a significant decrease in both groups, the difference between the two groups at the end of the fourth course was not significant. Neither group experienced any adverse effects. Although chamomile oral solution did not significantly lessen neuropathy, findings propose that it may significantly ameliorate sleep quality in patients receiving chemotherapy as a low-cost, low-risk treatment. It also has no significant impact on reducing the level of anxiety in cancer patients.

Isovanillin, a natural coumarin compound, exhibits biological functions; however, its anti-gastric cancer process is not well understood. This research examined the pathway underlying isovanillin's effects on gastric cancer cells. Cell viability assays demonstrated that isovanillin effectively reduced the viability of various gastric cancer cell lines. Network pharmacological analysis identified 41 key targets implicated in isovanillin's anti-gastric cancer activity, highlighting the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), mitogen-activated protein kinase (MAPK), and reactive oxygen species (ROS) pathways as critical components. Apoptosis assays revealed that isovanillin promoted apoptosis by upregulating the manifestation of p-p38 and p-JNK and suppressing p-ERK and p-STAT3. Cellular cycle examination revealed that isovanillin triggered G2/M stage block via the suppression of p-PI3K, p-AKT, cell cycle regulators 1/2 (CDK1/2), and cyclin B1, and the increase of cell cycle inhibitor 1A (p21) and cell cycle inhibitor 1B (p27). Cell metastasis assays showed that isovanillin suppressed the migration of MKN-45 cells through diminishing the concentrations of p-PI3K, p-AKT, N-cadherin, matrix metalloproteinase-2, as well as matrix metalloproteinase-9, while increasing E-cadherin expression. Furthermore, isovanillin exerted its anti-gastric cancer effects by promoting ROS accumulation, thereby modulating associated signaling pathways. The ROS scavenger N-acetyl-l-cysteine reversed isovanillin-induced protein expression changes. In conclusion, isovanillin induces apoptosis, G2/M phase arrest, and inhibits MKN-45 cell migration by mediating ROS to regulate the MAPK and PI3K signaling pathways.

Neuroblastoma is one of the most common extracranial solid tumors in children, characterized by high heterogeneity, aggressive biological behavior, and poor clinical prognosis. Ferroptosis, a form of programmed cell death driven by iron accumulation and lipid peroxidation, has been reported to be closely associated with neuroblastoma progression. Dauricine (Dau), a bisbenzylisoquinoline alkaloid extracted from traditional Chinese medicine, has demonstrated antitumor activity, but its role in regulating ferroptosis in neuroblastoma remains unclear. Cell viability, apoptosis, invasion, stemness, and angiogenesis were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, terminal deoxynucleotidyl transferase dUTP nick end labeling, transwell, sphere formation, and tube formation assays, respectively. Ferroptosis-related indicators were detected using corresponding commercial kits. The methyltransferase-like 1 (METTL1)-mediated N7-methylguanosine (m7G) methylation of solute carrier family 3 member 2 (SLC3A2) was examined through methylated RNA immunoprecipitation. RNA immunoprecipitation and RNA pull-down assays were conducted to confirm the interaction between METTL1 and SLC3A2 mRNA. Real-time quantitative PCR and western blotting were utilized to assess mRNA and protein expression, respectively. Molecular docking was performed to evaluate the potential binding interaction between Dau and METTL1. A xenograft tumor model was used for in vivo validation. The results showed that Dau inhibited neuroblastoma cell progression and promoted ferroptosis, while overexpression of SLC3A2 countered these effects. METTL1 mediated the m7G methylation of SLC3A2. Overexpression of SLC3A2 reversed the inhibition of neuroblastoma cell progression and the promotion of ferroptosis caused by METTL1 knockdown. Dau suppressed METTL1 expression, thus inhibiting neuroblastoma cell progression and promoting ferroptosis. Additionally, Dau reduced tumor growth in vivo. Together, Dau enhanced ferroptosis and impeded neuroblastoma development by suppressing METTL1-mediated m7G methylation of SLC3A2, suggesting a novel therapeutic strategy for neuroblastoma.

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy originating from the malignant clonal proliferation of hematopoietic stem/progenitor cells and is associated with a poor prognosis. Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a member of the MAP4K family, plays a critical role in immunomodulation and oncogenesis. Previous studies have highlighted its pro-oncogenic function in AML, suggesting its potential as both a prognostic marker and therapeutic target. This study aimed to investigate the anti-AML effects of the novel HPK1 inhibitor BGB-15025. We utilized preclinical models, including AML cell lines, primary patient-derived cells, and MV4-11 xenograft mice. Mechanistic investigations were conducted using RNA sequencing and Western blot analysis. BGB-15025 exerted potent cytotoxicity against AML cells and primary progenitors, inducing apoptosis and G0/G1 cell cycle arrest via downregulation of cyclin D1-cyclin-dependent kinase 4 and upregulation of P21. The inhibitor suppressed mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling through reduced phosphorylation of P38 and ERK. In-vivo studies demonstrated a reduced leukemia burden in xenograft models. This study is the first to elucidate that BGB-15025 triggers AML apoptosis through cell cycle blockade and MAPK pathway inhibition, thereby proposing a novel precision therapeutic strategy with significant clinical translational value.

Advanced gastric cancer (AGC) remains associated with poor survival despite advances in multimodal treatment. Recent trials suggest that adding programmed death-1 inhibitors to chemotherapy may improve outcomes in HER2-negative AGC, but real-world evidence-particularly in surgical settings-remains limited. This retrospective study evaluated the efficacy and safety of SOX plus sintilimab compared with P-SOX in patients with AGC undergoing perioperative chemotherapy followed by standard D2 gastrectomy. A total of 242 patients were included, of whom 161 received P-SOX and 81 received SOX plus sintilimab. Short-term response, long-term survival outcomes, and treatment-related adverse events were compared between groups. Prognostic factors for progression-free survival (PFS) were further analyzed in patients treated with SOX plus sintilimab. The SOX plus sintilimab regimen achieved superior short-term efficacy, with higher objective response rates by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (70.4% vs. 47.2%) and higher tumor regression grades (91.4% vs. 72.7%) compared with P-SOX (both P < 0.001). Median overall survival was significantly longer in the SOX plus sintilimab group (32.0 vs. 29.0 months; HR = 0.617, P = 0.006), while PFS showed a borderline improvement. Treatment-related adverse events were mostly grade 1-2, with comparable rates of severe toxicities between groups; immune-related events were infrequent. Poor perioperative treatment response, larger tumor size, poor differentiation, and advanced stage were independently associated with worse PFS. In conclusion, SOX plus sintilimab offers improved efficacy with acceptable safety compared with P-SOX, providing supportive real-world evidence for its use in AGC.

This study evaluated the efficacy and safety of fulvestrant combined with abemaciclib in patients with hormone receptor-positive advanced breast cancer and compared the outcomes with those reported in the MONARCH 2 trial. Forty-six patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer received fulvestrant 500 mg administered intramuscularly (days 1, 15, and 28, then every 28 days) combined with abemaciclib 150 mg taken orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. All 46 patients were evaluable for efficacy. No complete response was observed; 21 patients (45.7%) achieved partial response, 8 (17.4%) had stable disease, and 17 (37.0%) experienced progressive disease (PD). The ORR was 45.7%, and the DCR was 63.0%. Median PFS was 19.1 months (95% confidence interval: 16.0-NR). Compared with the MONARCH 2 trial, ORR was slightly higher (45.7% vs. 35.2%), whereas the DCR was lower (63.0% vs. 83.0%), accompanied by a markedly higher PD rate (37.0% vs. 9.0%, P < 0.001). The most frequently reported adverse events were leukopenia (30.4%), nausea/vomiting (47.8%), and fatigue (32.6%), consistent with findings from MONARCH 2, with no new safety signals identified. Fulvestrant combined with abemaciclib demonstrated antineoplastic activity and a manageable safety profile in patients with hormone receptor-positive advanced breast cancer. Relative to the MONARCH 2 trial, this real-world cohort exhibited a higher ORR but a lower DCR, potentially reflecting differences in prior treatments and baseline characteristics. Additional large-scale, multicenter studies are warranted to validate these findings.

This is the first global report of a successful case of lenvatinib treatment for a rare sebaceous carcinoma originating in the external auditory canal. The patient experienced local recurrence and pulmonary metastasis despite undergoing surgery and radiotherapy. Initial chemotherapy combined with immune checkpoint inhibitors achieved short-term stability, but the disease eventually progressed. Genetic testing revealed an Fibroblast growth factor receptor 2 (FGFR2) mutation, leading to a switch to targeted therapy with lenvatinib combined with capecitabine, demonstrating the value of targeted therapy in the management of rare, refractory sebaceous carcinoma.

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer that is characterized by rapid growth. PLCG2 is an enzyme that plays a crucial role in intracellular signal transduction pathways. This study aims to discover the role of PLCG2 in SCLC and the underlying mechanism. Relative expression of PLCG2 was detected by reverse transcription-quantitative PCR and Western blot. Cell viability, proliferation, and apoptosis were assessed by cell counting kit-8, colony formation, and flow cytometry assays. Mitophagy-related protein levels were analyzed by Western blot. RNA immunoprecipitation and dual-luciferase reporter assays were used to analyze the interaction between PLCG2 and VCP . A xenograft mouse model was established to analyze the role of PLCG2 in vivo . Results showed that PLCG2 was upregulated in SCLC tissues and cells, with high diagnostic potential. Besides, PLCG2 deficiency inhibited cell survival and mitophagy and promoted apoptosis in SCLC cells. In addition, PLCG2 interacted with VCP , and VCP overexpression reversed the inhibitory effects of PLCG2 silencing. In vivo , PLCG2 silencing suppressed SCLC tumor growth. In conclusion, PLCG2 is a promising biomarker for SCLC diagnosis and might be a potential therapeutic target, with its interaction with VCP playing a role in SCLC cell survival and mitophagy.