Anticancer research最新文献

Background/aim: Leukemia therapy targets multiple molecular pathways, including non-oncogenic but clinically relevant factors such as Silent Information Regulator 1 (SIRT1), which acts either as a tumor suppressor or tumor promoter depending on its downstream targets, cancer type, and disease stage. Although small-molecule SIRT1 activators such as SRT-1720 have shown anticancer potential, their molecular mechanisms in leukemia remain insufficiently understood. This study aimed to elucidate the effects of SRT-1720 on the redox state and viability of leukemic lymphocytes and normal lymphocytes, as well as its ability to sensitize leukemic cells to anticancer drugs.

Materials and methods: The synergistic, additive or antagonistic antiproliferative effects of SRT-1720 and anticancer drugs were examined. The following parameters were analyzed: cell viability and proliferation - by trypan blue staining; apoptosis - by phosphatidylserine expression on the cell surface; and oxidative stress - by detecting intracellular levels of reactive oxygen species (ROS) and protein carbonyl products.

Results: SRT-1720 potentiated the effects of most anticancer drugs in leukemic lymphocytes. Synergism was found in combination with: barasertib, bortezomib, cisplatin, MG-132, bleomycin, ABT-737, lonafarnib, everolimus, and palbociclib. SRT-1720 increased the tolerance of normal lymphocytes to anticancer drugs, as demonstrated for everolimus, barasertib, and doxorubicin. The synergistic cytotoxicity of SRT-1720 in combination with everolimus and barasertib was accompanied by overproduction of ROS and increased induction of apoptosis in leukemic lymphocytes, but not in normal lymphocytes. SRT-1720 favorably affected the viability of normal lymphocytes, reducing oxidative stress and cytotoxicity induced by doxorubicin at the concentrations used in our study.

Conclusion: SRT-1720 induces oxidative stress and apoptosis in leukemic lymphocytes through SIRT1-independent pathway(s). In contrast, it enhances antioxidant defense in normal lymphocytes through a SIRT1-dependent pathway. These findings highlight the potential of SRT-1720 as an adjuvant to chemotherapy in T-ALL, particularly in drug combinations demonstrating strong synergism, which may allow dose reduction and decreased toxicity.

Background/aim: Glutamine (GLN) addiction has been proposed as a cancer vulnerability and a therapeutic target. However, the glutamine requirement of normal cells is poorly understood. In the present study, we used a unique co-culture model to study the glutamine requirement of cancer cells compared to normal cells co-cultured together.

Materials and methods: The human fibrosarcoma cell line HT1080 and normal human fibroblasts HS27 were co-cultured in 12-well dishes seeded with equal numbers of cells of each type. Additionally, HS27 cells were cultured alone in 6-well plates. The cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) which did not contain GLN, methionine (MET), or cystine (CYS). 150 μM L-cystine 2HCl was added to all media. Co- and mono- cultures were grown under the following conditions: Complete medium (GLN 4 mM and MET 100 μM); MET restriction [Methionine restriction (MR), GLN 4 mM and MET 0 μM]; GLN restriction [Glutamine restriction (GR), GLN 0 mM and MET 100 μM] and MR+GR (GLN 0 mM and MET 0 μM). Cells were observed under phase-contrast and fluorescence microscopy for seven days. ImageJ was used to compare the three groups: MR, GR and MR+GR.

Results: In complete DMEM, HT1080 fibrosarcoma cells dominated HS27 normal fibroblasts in co-culture. Under MR, HT1080 cells became mostly non viable, but HS27 cells remained viable. Under GR and MR+GR, both HT1080 and HS27 cells became mostly non-viable. Monoculture experiments showed that normal cells survived under MR but not GR.

Conclusion: GR is not a cancer-specific vulnerability, while MR is. Therefore, GR is not a promising cancer-therapy strategy.

Background/aim: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, and lung metastasis is the major cause of death. Highly metastatic osteosarcoma cells are mechanically softer than low-metastatic cells, and calcium ions are known to regulate cytoskeletal organization and cell stiffness. We tested whether clinically available ion channel blockers could increase the stiffness of LM8 osteosarcoma cells and prevent lung metastasis in vivo.

Materials and methods: We evaluated the actin cytoskeletal structure and polymerization in ion channel blocker-treated LM8 cells using actin staining. Cell stiffness was measured using atomic force microscopy. Metastasis-related cellular functions were analyzed using cell proliferation, wound healing, and cell adhesion assays. Furthermore, lung metastasis and tumor volume were measured in LM8-bearing mice treated with an ion channel blocker.

Results: Treatment with ion channel blockers significantly increased actin staining intensity and stiffness in LM8 cells compared to that in untreated LM8 cells (p<0.05). The proliferation potential was significantly lower in the amlodipine-treated group (p<0.05). The ion channel blockers treatment group demonstrated significantly higher adhesion than the control group (p<0.05). The migration potential of the disopyramide- and lidocaine-treated groups were lower than that of the control group. Daily intraperitoneal administration of 20 mg/kg amlodipine for five weeks in LM8-bearing mice significantly reduced lung metastasis compared to that in the control group (p<0.05). No significant differences in tumor volume were observed after amlodipine administration.

Conclusion: Amlodipine could increase tumor cell stiffness and significantly reduce lung metastasis.

Background/aim: Triplet therapy, combining androgen deprivation therapy (ADT), darolutamide, and docetaxel has recently emerged as the standard first-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC). Febrile neutropenia (FN) is a major clinical issue not only as a serious infection but also as a cause for early cessation or dose reduction of chemotherapy. However, little is known regarding the predictive factors for the development of FN in patients with mHSPC receiving triplet therapy.

Patients and methods: This study enrolled 60 patients diagnosed with mHSPC across multiple institutions from 2023 to 2025. We examined clinical characteristics, treatment schedules, adverse events, and oncological outcomes. We focused particularly on the development of FN and used logistic regression analysis to investigate the predictive factors.

Results: The median age was 72 years old, and 43 patients (73.3%) had high-volume disease at diagnosis. Nine patients (15%) developed FN. Multivariate logistic regression analysis identified older age [≥75, p=0.0161; hazard ratio (HR)=7.49], high-volume disease (p=0.0335), and shorter interval from ADT to docetaxel (<40 days) (p=0.0389; HR=7.86) as independent predictive factors of the development of FN. Notably, prolonged castration period prior to docetaxel (≥40 days) significantly reduced the risk of FN from 23.5% to 3.8% (p=0.0001). Patients who developed FN tended to have shorter castration-resistant prostate cancer progression-free survival (CRPC-PFS) compared to those who did not (p=0.0812; HR=3.2).

Conclusion: Older age and high-volume disease were independent risk factors for FN in patients with mHSPC receiving triplet therapy. A longer interval from ADT initiation to docetaxel (≥40 days) was associated with a significantly lower risk of FN, suggesting that extending the pre-docetaxel castration period is a practical, adjustable scheduling strategy to improve treatment safety. These findings may support treatment selection and proactive prevention of FN.

Background/aim: The mesenchymal-epithelial transition (MET) receptor plays a key role in cell growth and survival. The MET exon 14 (METex14) skipping mutation occurs in 3% to 4% of patients with non-small cell lung cancer (NSCLC) and leads to prolonged MET signaling and oncogenesis. MET tyrosine kinase inhibitors (TKIs), such as tepotinib and capmatinib, are effective for METex14-altered NSCLC; however, their impact on patients with a poor performance status (PS) is unclear. We retrospectively analyzed clinical outcomes of MET-TKI treatment for NSCLC with the METex14 skipping mutation.

Patients and methods: We reviewed 59 cases of NSCLC with the METex14 skipping mutation diagnosed at the National Cancer Center Hospital between June 2020 and April 2024. Clinical data included demographics, PS, histology, PD-L1 expression, treatment response, progression-free survival (PFS), and overall survival (OS).

Results: Forty-nine patients (median age, 72 years; range=50-87 years; 53.1% male) received MET-TKIs (tepotinib or capmatinib). Thirty-seven patients and 12 patients had PS scores of 0 or 1 and ≥2, respectively. The median PFS and median OS of patients who received MET-TKI treatment were 5.6 months and 18.7 months, respectively. Thirty-seven patients who received first-line MET-TKI treatment had median PFS, median OS, and a median overall response rate (ORR) of 5.6 months, 21.3 months, and 48.6%, respectively. For patients with a PS score ≥2 (n=9), the median PFS, median OS, and median ORR were 0.95 months, 1.3 months, and 11.1%, respectively. A PS score ≥2 was strongly associated with shorter OS. Two of nine (22.2%) patients with a poor PS experienced improvement.

Conclusion: MET-TKIs are effective for NSCLC with the METex14 skipping mutation; however, their efficacy for patients with a poor PS is limited.

Background/aim: Cyclin-dependent kinase 1 (CDK1) is a regulator of the G₂-M transition whose dysregulation undermines cell-cycle fidelity and drives malignant growth. Although CDK1 has been implicated in tumorigenesis, its prognostic value varies by cancer type. Here we analyzed the prognostic landscape of CDK1 across human cancers and prioritized on therapeutic candidates for cancer types in which CDK1 is most strongly implicated.

Materials and methods: We performed a pan-cancer analysis of CDK1 expression across 31 tumor types from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx), and tested associations with outcome by univariate Cox regression and Kaplan-Meier analysis. To translate these findings into therapeutic insights, we carried out structure-based virtual screening of a curated natural-product library against the CDK1 ATP-binding pocket and assessed predicted binding affinity.

Results: CDK1 was broadly overexpressed across multiple malignancies and high CDK1 expression associated with poorer survival in several tumor cohorts. Adrenocortical carcinoma (ACC) showed one of the strongest and most consistent prognostic associations, with CDK1 expression rising with advancing stage. Structure-based screening nominated five natural compounds namely, Salvianolic acid C, Salvianolic acid A, Calceolarioside B, Chicoric acid, and Plantagoside, as promising CDK1 kinase inhibitors and drug candidates for ACC. These compounds demonstrated favorable CDK1 binding and possess reported biological and anticancer activities, supporting their translational potential.

Conclusion: Our findings highlight CDK1 as a prognostic marker and a therapeutic target across multiple cancers, with particular relevance in ACC. By integrating pan-cancer transcriptomic analysis with structure-based drug discovery, this study not only emphasizes the clinical significance of CDK1 in ACC but also proposes natural compound-derived inhibitors as promising candidates for future therapeutic development.

Background/aim: Lenvatinib, a multikinase inhibitor, has shown potential anti-tumor activity in various cancers. This study evaluated its efficacy, safety, and apoptotic mechanisms in colorectal cancer (CRC) using HT-29 xenograft-bearing mice.

Materials and methods: Mice were treated with lenvatinib at 0, 10, or 20 mg/kg for 20 days. Tumor growth, serum biochemistry, and histopathology were assessed. Protein expression related to ERK signaling and apoptosis was analyzed using immunohistochemistry.

Results: Lenvatinib significantly suppressed CRC tumor growth, delaying progression up to 14-fold compared with controls. No body-weight loss or hepatic/renal toxicity was observed, indicating good tolerability. Mechanistically, lenvatinib reduced phosphorylated ERK and anti-apoptotic proteins (BCL-2, c-FLIP, XIAP) by 30-50%, while enhancing cleaved caspase-3, -8, -9, BAX, and BAK expression by 1.2-1.5-fold, promoting apoptosis.

Conclusion: Lenvatinib exhibits potent anti-CRC activity with minimal systemic toxicity. Its therapeutic effects are mediated through ERK pathway inactivation, suppression of anti-apoptotic proteins, and induction of caspase-dependent apoptosis.

Background/aim: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Among its genetic subtypes, KMT2A (formerly MLL)-rearranged ALL (KMT2Ar-ALL) is associated with poor outcomes. Immunotherapy approaches are being studied and used in KMT2Ar-ALL; however, there is evidence that leukemic cells can escape immune control. Our previous study identified Galectin-1, an immune checkpoint protein, as highly expressed in KMT2Ar-ALL, suggesting it as a potential therapeutic target. To date, the exact mechanism of Galectin-1 regulation in KMT2Ar-ALL is unknown. Therefore, the present study aimed to investigate the potential involvement of the mTOR signaling pathway in the regulation of Galectin-1 expression in KMT2Ar-ALL.

Materials and methods: The study employed both in silico and in vitro approaches: gene expression data from B-cell acute lymphoblastic leukemia subtypes were analyzed bioinformatically, while four leukemia cell lines (RS4;11, SEMK2, SUP-B15, and NB-4) were treated with the mTOR inhibitor everolimus to evaluate its effect on Galectin-1 expression at the mRNA and protein levels, using qPCR and immunoblotting. Transcription factor binding on the LGALS1 promoter was assessed with computational tools.

Results: Galectin-1 mRNA and protein were selectively upregulated in KMT2Ar-ALL cells, and inhibition of the mTOR pathway with everolimus modulated Galectin-1 expression in these cells. A novel putative transcription factor, SP1, was proposed, which may bind to the Galectin-1 promoter and can be regulated by the mTOR pathway.

Conclusion: Targeting mTOR signaling contributes to the regulation of Galectin-1 immune checkpoint activity in KMT2Ar-ALL. Inhibition of mTOR may represent a potential therapeutic strategy to overcome immune evasion in this leukemia subtype.

Background/aim: Uterine cancer is the fourth most frequently diagnosed cancer in women, and continues to present significant clinical challenges, particularly in older populations. Tumor progression is tightly linked to metabolic adaptations, and emerging evidence points to an association between dysregulated vitamin B2 (riboflavin, Rf) metabolism and cancer development. Rf is an essential precursor of the flavin cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are critical for cellular energy metabolism and redox balance. The aim of the study was to investigate whether uterine cancer tissues exhibit alterations in the expression of key regulators of flavin homeostasis - riboflavin transporters (RFVT1-3) and FAD synthase (FADS) - and to determine how these changes relate to intracellular flavin levels and to the expression of the FAD-dependent epigenetic enzyme lysine-specific demethylase 1 (LSD1).

Materials and methods: Paired samples of tumor tissue and surrounding normal mucosa from eight patients with uterine cancer were analyzed to evaluate the expression of: RFVTs by both RT-PCR and western blot; and FADS, and the FAD dependent enzyme lysine specific demethylase 1 (LSD1) by RT-PCR. Furthermore, we evaluated flavin cofactors levels by HPLC.

Results: Quantitative analyses revealed a significant up-regulation of RFVT1 and RFVT3 at both mRNA and protein levels in tumor tissues, accompanied by markedly increased intracellular levels of Rf (3fold) and FAD (2.5fold). FADS, the enzyme responsible for FAD production and delivery to client flavoproteins, was also significantly overexpressed and correlated with elevated LSD1 expression.

Conclusion: A coordinated mechanism where uterine cancer cells adaptively up-regulate RFVTs, FADS, and LSD1 to meet their metabolic demands was revealed. These results provide insights into the metabolic vulnerabilities of uterine cancer and propose Rf metabolism and flavin-dependent processes as potential therapeutic targets.

Background/aim: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, characterized by aggressive progression, profound chemoresistance and unique metabolic adaptations such as elevated autophagy. Although the splicing factor SF3B4 has been reported to function as an oncogene in other malignancies, its role in PDAC remains unclear. This study aimed to elucidate the functional and mechanistic significance of SF3B4 in PDAC.

Materials and methods: SF3B4 expression in PDAC was analyzed using patient datasets and experimental models. Functional assays including cell proliferation, colony formation, migration, and autophagy analyses were performed in PDAC cells. Reactive oxygen species (ROS) levels were evaluated. Sensitivity to 5-fluorouracil (5-FU) and apoptotic responses were also evaluated.

Results: SF3B4 acts as a tumor suppressor in PDAC by inhibiting autophagy, a process that this cancer uniquely depends on for survival. SF3B4 overexpression inhibited proliferation, colony formation and migration of PDAC cells. Mechanistically, SF3B4 suppressed autophagic flux, resulting in increased ROS accumulation and subsequent inhibition of tumorigenic phenotypes. Treatment with the antioxidant N-acetylcysteine (NAC) rescued the tumor suppressive effects of SF3B4 overexpression. Moreover, SF3B4 overexpression sensitized PDAC cells to 5-FU, accompanied by enhanced apoptotic responses.

Conclusion: SF3B4 is a context-dependent splicing factor that functions as a tumor suppressor in PDAC by regulating autophagy and redox homeostasis. Targeting the SF3B4-autophagy-ROS axis may represent a promising strategy to suppress PDAC progression and overcome chemoresistance.