Anticancer research最新文献

Background/aim: The combination of enfortumab vedotin (EV) and pembrolizumab (P) has been recently established as the standard first-line treatment for advanced urothelial carcinoma. While the safety profiles of individual agents are well-characterized - EV with cutaneous toxicity and pembrolizumab with immune-related adverse events (irAEs), severe esophageal involvement remains an exceedingly rare and poorly understood complication. To our knowledge, this is the first detailed report of esophageal ulceration specifically associated with EV+P combination therapy.

Case report: A 67-year-old woman with metastatic urothelial carcinoma originating from the ureter and liver metastases was treated with EV+P therapy. On day 12 of the first cycle, she developed a mild Grade 1 drug rash. However, on day 21, she presented with new-onset severe odynophagia and dysphagia (CTCAE Grade 3), preventing the intake of solids and liquids. Upper gastrointestinal endoscopy revealed diffuse, deep ulcerations throughout the esophagus. Infectious etiologies, including herpes simplex virus, cytomegalovirus, and Candida, were definitively excluded. The condition was diagnosed as a severe immune-mediated or treatment-related mucosal injury. EV+P was withheld, and systemic corticosteroids (prednisolone 1 mg/kg/day) were initiated alongside proton pump inhibitors. Symptoms improved rapidly within 72 h. Follow-up endoscopy at eight weeks confirmed complete resolution of the ulcers. Although the primary tumor and liver metastases showed marked shrinkage, new bone metastases appeared. EV+P was subsequently resumed without recurrence of esophageal symptoms.

Conclusion: Clinicians must be vigilant for severe esophageal toxicity during EV+P therapy. While pembrolizumab-induced irAE is the primary suspect, EV-associated mucocutaneous toxicity remains a potential differential diagnosis. Early recognition and prompt high-dose corticosteroid therapy can lead to successful management without permanent sequelae.

Background/aim: Cholangiocarcinoma (CCA) is a highly aggressive cancer for which current chemotherapies offer limited effectiveness. However, recent research suggests a promising new approach using adenosine. Studies have shown that adenosine can inhibit CCA cell growth while having minimal harmful effects on immortalized cholangiocytes (imCho). This particular study delved deeper into these findings, investigating the specific effects of adenosine on CCA and imCho to better understand its therapeutic potential against this disease.

Materials and methods: Cell growth was examined using the MTT assay. Cell invasion was examined using the transwell assay. Cell death was evaluated using flow cytometry. Protein levels were examined using western blot analysis. Animal experiment was performed in Balb/cAJcl-Nu mice.

Results: Adenosine demonstrated differential effects on CCA cells compared to imCho. Specifically, adenosine induced endoplasmic reticulum (ER) stress in CCA cells but not in imCho. When combined with hydroxychloroquine (an autophagy inhibitor), apoptosis was greatly enhanced in CCA cells. This combination exhibited a more pronounced deleterious effect on CCA cells than on imCho cells, suggesting a potential for selective targeting. While adenosine alone demonstrated the ability to slow CCA growth in vitro, it did not induce apoptosis in this setting. However, in vivo tumor xenograft studies revealed comparable tumor sizes between adenosine monotherapy and the adenosine-hydroxychloroquine combination. Notably, the combination group exhibited a higher number of apoptotic cells. Further investigation into the molecular mechanisms revealed that adenosine activated both AMPK and mTORC1 signaling pathways. Crucially, the mTORC1 pathway was found to be essential for adenosine's ability to inhibit CCA cell growth and invasion.

Conclusion: A co-activation of AMPK and mTORC1 signaling pathways in CCA cells after adenosine treatment. Both pathways are necessary for adenosine to inhibit CCA cell growth and invasion.

Background/aim: Maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) measured using whole-body positron emission tomography (PET) have attracted attention as prognostic parameters. Dedicated breast PET (dbPET), a high-resolution imaging modality, is expected to accurately reflect the metabolic parameters of breast tumors. This study aimed to investigate the prognostic value of metabolic parameters on dbPET for breast cancer.

Patients and methods: Ninety-six patients with luminal invasive breast cancer who underwent surgery were analyzed. SUVmax, MTV, and TLG were measured from dbPET images obtained before treatment. The associations between each parameter and recurrence-free survival (RFS) were evaluated.

Results: During a median follow-up of 8.4 years, eight (8.3%) patients experienced recurrence. The median dbPET values were SUVmax 6.75, MTV 0.64 cm³, and TLG 2.56 cm³. Patients with high SUVmax, MTV, and TLG showed poorer RFS than those with low values: 8-year RFS was 81.9% vs. 96.3% for SUVmax (p=0.004), 68.8% vs. 96.0% for MTV (p<0.001), and 75.1% vs. 96.0% for TLG (p<0.001). Multivariate analysis identified high TLG [hazard ratio (HR)=7.81, 95% confidence interval (CI)=1.19-51.4, p=0.033] and lymphatic invasion (HR=6.64, 95% CI=1.05-41.9, p=0.044) as independent predictors of unfavorable RFS. Multiple regression models suggested that TLG was the most promising parameter for predicting RFS.

Conclusion: Metabolic parameters on dbPET, particularly TLG, are potentially useful for predicting the prognosis of luminal breast cancer.

Background/aim: Although immunotherapies such as atezolizumab plus bevacizumab (Ate/Bev) and tremelimumab plus durvalumab (Tre/Dur) are recommended as first-line treatments for unresectable hepatocellular carcinoma (uHCC), the clinical utility of Tre/Dur as first- or second-line therapy for uHCC remains debatable. We studied the clinical utility of first-line Tre/Dur treatment for uHCC using serum cytokine profiles.

Patients and methods: We analyzed preserved serum of adult Japanese patients with liver cirrhosis and uHCC from a previous prospective study who received Tre/Dur at our hospital. Blood samples were collected before and after four weeks of treatment. Dynamic computed tomography (CT) was performed after 8-12 weeks of treatment to assess the response.

Results: Among nine non-immunotherapy (non-IO) group patients, three, five, and one patients showed partial response (PR), stable disease (SD), and progressive disease (PD), respectively, whereas none of the 10 IO group patients showed PR; three and seven patients showed SD and PD, respectively. Serum tumor necrosis factor (TNF)-alpha and soluble IL-2 receptor (IL-2R) increased significantly in both groups, with no significant changes in interleukin (IL)-6 levels in both groups. No significant difference was noted in serum MHC class I levels before and after treatment in either group, whereas soluble programmed cell death ligand 1 (sPD-L1) level increased in both groups. However, serum soluble MHC class I and sPD-L1 levels before treatment were higher in the IO group than in the non-IO group.

Conclusion: A history of Ate/Bev therapy increased soluble MHC class I and sPD-L1 serum levels. Tre/Dur therapy may be useful as a first-line treatment for uHCC, and elevated sPD-L1 levels may attenuate Dur efficacy. This increase may impair tumor recognition and potentially reduce Tre/Dur therapy effectiveness despite activated cytotoxic T cells.

Background/aim: Metabolic alterations resulting from mutation in tricarboxylic acid cycle enzymes such as isocitrate dehydrogenase 1 (IDH1) have been observed in various cancers. These alterations can be exploited as therapeutic targets to induce metabolic synthetic lethality. This study aimed to characterize the metabolic signature of cholangiocarcinoma (CCA) carrying an IDH mutation and investigate a novel anti-cancer mechanism of erlotinib in inducing cancer cell death through the regulation of altered metabolism.

Materials and methods: Two CCA cell lines were used: SNU-1079, carrying an IDH1 mutation, and SNU-1196, IDH1 wild-type. Metabolic alterations were validated using liquid chromatography-tandem mass spectrometry. The anti-tumor effects of erlotinib on CCA cell lines were evaluated using cell viability, colony formation, and Annexin V/PI staining assays. Mitochondrial physiology was assessed via microscopy and cytofluorometry following MitoTracker loading. Lysosome swelling was confirmed by detecting cytosolic cathepsin B via western blot and immunocytochemistry using LysoTracker.

Results: SNU-1079 cells exhibited a mitochondria-independent metabolic feature, suggesting functional mitochondrial alteration. The mitochondrial membrane potential was disrupted, and mitochondrial length was reduced in SNU-1079 cells. This cell line utilized NIX-mediated mitophagy through hyperactivated epidermal growth factor receptor (EGFR) signaling. Erlotinib inhibited EGFR signaling and induced SNU-1079 cell death by interrupting the mitophagic flux. The blockage of mitophagy by erlotinib was associated with lysosomal swelling, indicated by the presence of cytosolic cathepsin B.

Conclusion: The CCA cell line carrying an IDH mutation utilized mitophagy as a novel metabolic compensatory mechanism activated through EGFR-specific signaling. Mitophagy acted as a metabolic synthetic lethality partner to the EGFR inhibitor erlotinib. These findings strongly suggest the potential of erlotinib as a therapeutic strategy for patients with IDH1-mutant CCA.

Background/aim: Metastatic osteolytic bone tumors represent a clinical challenge as their pathogenesis and progression involve complex interactions within the bone microenvironment. Sclerostin, a key inhibitor of the Wnt signaling pathway, is critical to bone metabolism; however, its involvement in metastatic bone tumors remains insufficiently characterized. This study investigated sclerostin's role in metastatic osteolytic tumors, specifically its relationship with other bone remodeling molecules, including DKK1, BMP6, and the proliferation marker Ki67.

Patients and methods: Tumor specimens were collected from nine patients who underwent surgery for metastatic bone tumors in the femur or tibia. Sclerostin, DKK1, BMP6, and Ki67 expression was assessed using immunohistochemical staining. Positivity rates were determined for each protein. Correlations between their expression levels were examined using Pearson's correlation coefficient.

Results: All tumor samples demonstrated a certain degree of positivity for sclerostin, DKK1, BMP6, and Ki67. The mean proportion of sclerostin-positive cells was 7.3%. Sclerostin and DKK1 exhibited a moderately negative correlation (r=-0.45), suggesting their distinct roles in the tumor microenvironment. Sclerostin and BMP6A exhibited a weak positive correlation (r=0.25), while sclerostin and Ki67 showed no significant correlation. The cohort's one-year survival rate was 72.9%.

Conclusion: Sclerostin contributes to the bone formation processes within the osteolytic metastatic tumor microenvironment, possibly through interactions with BMP6 and modulation of Wnt signaling, thus highlighting its potential as a novel therapeutic target for the treatment of metastatic bone tumors. Further studies with larger, more homogeneous patient cohorts are warranted to validate these findings and elucidate the precise molecular mechanisms involved.

Background/aim: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy often characterized by poor response to conventional therapies and frequent relapse. Ponatinib, a third-generation tyrosine kinase inhibitor, has demonstrated efficacy in various leukemias but remains underexplored in AML. Vitamin K2 (VK2), a fat-soluble vitamin, has recently been implicated in inducing apoptosis in leukemia cells. This study aimed to evaluate the therapeutic potential of ponatinib and VK2, alone and in combination, across five AML cell lines.

Materials and methods: SKM-1 (myelodysplastic syndrome cell line) and AML cell lines MOLM-14, Kasumi-1, THP-1, and MV4-11 were tested. Cells were plated in 96-well plates and exposed to ponatinib or VK2, and cell viability and cytotoxicity were assessed. After 48 or 72 h of incubation, luminescence or absorbance was recorded, and cell numbers were quantified. Cells were plated in MethoCult medium supplemented with the indicated drug concentrations and incubated for 10 days at 37°C in a humidified 5% CO₂ atmosphere. Colonies containing more than 50 cells were enumerated, and representative images were captured. Caspase-3/7 activity was measured after 48 h of drug exposure, and luminescence signals were detected. Cells were stained with the JC-1 MitoMP Detection Kit and analyzed using a fluorescence microplate reader. Mitochondrial membrane potential was determined by calculating the ratio of red to green fluorescence intensity. Intracellular adenosine triphosphate levels were quantified.

Results: Ponatinib exhibited cell line-dependent cytotoxic effects, with MOLM-14 and MV4-11 being the most sensitive. VK2 suppressed cell viability in all tested lines, with synergistic enhancement when combined with ponatinib. The combination treatment significantly increased apoptosis, reduced colony formation, and disrupted mitochondrial membrane potential.

Conclusion: The combined ponatinib and VK2 treatment synergistically impairs AML cell survival by enhancing apoptosis, suppressing clonogenic growth, and disrupting mitochondrial function. This dual targeting of oncogenic kinase signaling and metabolic integrity supports the ponatinib-VK2 combination as a promising therapeutic strategy for AML.

Background/aim: Glioblastoma (GBM) cells that adapt to the in vivo microenvironment often display enhanced invasion driven by EGFR-ERK signaling and epithelial-mesenchymal transition (EMT). This study aimed to characterize an EGFR-ERK-dependent T98G subline (T98G-xeno) and to determine how gallic acid (GA) modulates reactive oxygen species (ROS), EGFR-ERK signaling, EMT and migration.

Materials and methods: Parental T98G and T98G-xeno cells were compared for proliferation, EMT markers and migration. GA cytotoxicity, ROS, EGFR-ERK signaling and migration were assessed after GA, EGF, N-acetyl-L-cysteine (NAC) or EGFR siRNA treatment.

Results: T98G-xeno cells showed faster growth, increased migration, higher levels of mesenchymal markers, and elevated basal p-EGFR/p-ERK ratio versus T98G cells. Non-apoptotic GA increased ROS, decreased p-EGFR/EGFR and p-ERK/ERK ratios, restored E-cadherin/ZO-1, reduced N-cadherin/vimentin and inhibited wound closure and migration. EGF-induced EGFR-ERK activation and migration were antagonized by GA. EGFR siRNA mimicked GA, whereas NAC attenuated GA-induced ROS and partially rescued these effects.

Conclusion: GA targets a ROS-EGFR-ERK-EMT axis in T98G-xeno cells, acting as a non-cytotoxic modulator that reverses EMT and limits migration. These findings suggest that GA-based strategies may help restrain invasion in EGFR-ERK-addicted, EMT-enriched GBM.

Background/aim: FAS/FAS-ligand (FAS-L) complex is implicated in critical cell functions including programmed cell death (apoptosis) and immune response regulation. FAS and FAS-ligand are members of the tumor necrosis factor (TNF) superfamily. Their activation triggers the caspase-mediated apoptotic cataract. The aim of this study was to investigate the role of their altered co-expression in a series of laryngeal squamous cell carcinomas (LSCCs).

Materials and methods: A set of fifty (n=50) LSCC archival tissue sections was analyzed by performing a combination of immunohistochemistry (IHC) and digital image analysis (DIA) assays for determining the expression of FAS/FAS-L expression.

Results: A broad spectrum of FAS/FAS-L expression values were detected across the examined cases. A significant negative correlation was found between FAS and FAS-L overall expression (p<0.001) indicating that higher FAS expression is associated with lower FAS-L expression. Furthermore, the expression of FAS was highest in stage IV carcinomas, whereas FAS-L was higher in stage III tumors, however, the differences were not statistically significant (p=0.260, p=0.101, respectively). Concerning the size of the examined malignancies (max diameter), the FAS/FAS-L expression showed a statistically significant difference in both (p=0.001, p=0.011, respectively). According to their expression status, larger tumors tend to demonstrate higher levels of FAS protein, whereas smaller tumors exhibit overexpression of FAS-L.

Conclusion: FAS/FAS-L apoptotic system deregulation is a relatively frequent event in LSCCs. Dysregulation of the system - due to altered FAS and FAS-L co-expression levels - negatively affects the normal apoptotic mechanism. Additionally, this abnormality is clearly observed in aggressive phenotypes (advanced stage, enlarged tumor volume).

Background/aim: Cancer has been described as the perennial second leading cause of death, despite advances in detection and treatment. Considering this disease remains a major public health crisis across the world, scientists have been looking for additional anticancer drugs options. In this context, the privileged scaffold quinoline appears to be an interesting chemical structure to develop new anticancer drugs, especially when more efficient synthetic routes to form these compounds are proposed.

Materials and methods: A total of five quinoline derivatives were obtained by applying the adapted methodology of Skraup and Doebner-von Miller and Heck-Mizoroki. The anticancer profile was investigated on cervical cancer (HeLa and Me-180) and chronic myeloid leukemia (K562) cell lines, by using the MTT or FACSVerse flow cytometer assays. Treatment of Vero cells was performed to assess the Selectivity Index, followed by the type of cell death assessment (apoptosis and necrosis) for the most active and safe derivative. ADMET profile was investigated by using SwissADME platform and DataWarrior^® software.

Results: The most promising result was achieved with derivative 3, with best antiproliferative activity especially against cervical cancer cell lines (HeLa: IC₅₀ 15.13 μM and Me-180: IC₅₀ 46.90 μM) and safe profile compared to Vero cells and in silico prediction. The type of cell death was mostly related to late apoptosis. All quinoline derivatives demonstrated druglikeness in agreement with Lipinski and Veber rules.

Conclusion: Our findings provide quinoline derivatives with anticancer activity, which may pave the way for new alternatives for anticancer drug development.