Anticancer research最新文献

Background/aim: Cancer remains a major global health concern due to its high mortality rates. Advanced diagnostic imaging, such as in vivo near-infrared (NIR) fluorescence imaging, enhances early detection by reducing autofluorescence and enabling deeper tissue penetration, addressing some limitations of conventional methods. Understanding the underlying causes of autofluorescence, even in mouse model fluorescence imaging, is crucial for accurate interpretation. This study investigated the origins of autofluorescence observed in experimental animals under NIR wavelengths, achieving successful fluorescence imaging in a clinically relevant tumor mouse model.

Materials and methods: Both fasting and non-fasting groups were evaluated to assess the dietary impact on autofluorescence, with various feeds tested. Subcutaneous and lung tumor models were established in C57BL/6 and BALB/c nude mice using LL/2-iRFP cells. Cryo-sectioning and lung tissue imaging were conducted to confirm tumor presence and assess fluorescence signals.

Results: It was found that autofluorescence, notably common in the abdomen, is attributed to dietary factors. By selecting feed that lacks autofluorescence, the impact of dietary fluorescence on imaging was evaluated, leading to the establishment of optimized imaging conditions suited to the presence or absence of autofluorescence. Subsequently, utilizing lung cancer cells expressing near-infrared proteins (LL/2-iRFP), intratracheal, and subcutaneous tumor mouse models were developed, and successful in vivo imaging was achieved using the optimized imaging protocols, effectively bypassing autofluorescence.

Conclusion: This study emphasizes the importance of understanding and addressing autofluorescence in fluorescence imaging, presenting valuable insights for enhancing the reliability and accuracy of diagnostic imaging techniques in cancer research and clinical practice.

Background/aim: The purpose of this study was to evaluate whether the sparing effect on cell survival is observed under normoxia.

Materials and methods: A superconducting spiral sector-type azimuthally varying field (AVF) cyclotron produced 230 MeV proton beams at 250 Gy/s as ultra-high dose rate (uHDR) and 1 Gy/s as normal dose rate (NDR) to irradiate tumor and normal cell lines (HSGc-c5 and HDF up to 24 Gy at the center of spread-out Bragg peak (SOBP). The Advanced Markus chamber and Gafchromic film were used to measure the examined absolute dose and field sizes. Colony formation assay and immunofluorescence staining were conducted to evaluate the sparing effect.

Results: A homogeneous field was achieved at the center of the SOBP for both uHDR and NDR scanned proton beams, and dose reproducibility and linearity were adequate for experiments. There were significant differences in cell surviving fractions of HSGc-C5 and HDF cells irradiated at uHDRs compared to NDRs at 20 Gy and 24 Gy. Increasing γ-H2AX foci were observed for both cell lines at NDR.

Conclusion: The sparing effect on cell survival was first observed under normoxic conditions for tumor and normal cells with doses exceeding 20 Gy, using proton irradiation at 250 Gy/s extracted from a superconducting AVF cyclotron. This study marks a significant milestone in advancing our understanding of the underlying mechanism behind the sparing effect.

Background/aim: Epithelial ovarian cancer (EOC) is a lethal disease that is the fifth leading cause of cancer-related death in women. BAF312 (siponimod) is a potent and selective sphingosine-1-phosphate (S1P) receptor modulator that has been approved as a treatment for multiple sclerosis. In addition to its immunomodulatory action, BAF312 shows preclinical antitumor effects in several cancer types. This study sought to determine whether BAF312 had anticancer properties against EOC using in vitro and in vivo models.

Materials and methods: EOC cell lines A2780, SKOV3ip1, A2780-CP20, and SKOV3-TR were treated with BAF312 and tested for cell proliferation, apoptosis, and migration using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, fluorescence-activated cell sorting, and migration assays. We investigated the expression of sphingosine-1-phosphate receptor 1 (S1PR1) in most EOC cell lines through western blot analysis. To investigate potential mechanisms, western blot analysis was used to assess the expression of AKT serine/threonine kinase 1 (AKT) and extracellular-regulated kinase (ERK) after BAF312 treatment. We also created poly(D,L-lactide-co-glycolide) nanoparticles encapsulating BAF312 (PLGA-NP-BAF312) for in vivo therapy. The average size and zeta potential of PLGA-NP-BAF312 were determined using dynamic light scattering. The therapeutic efficacy of PLGA-NP-BAF312 was tested in an A2780 tumor-bearing orthotopic mouse model of EOC.

Results: S1PR1 was overexpressed in most EOC cell lines. BAF312 significantly reduced cell proliferation and migration while inducing significant apoptosis in all EOC cell lines. PLGA-NP-BAF312 treatment significantly reduced tumor weights in A2780 tumor-bearing mice. Furthermore, the anticancer effects of BAF312 were associated with reduced phosphorylation of ERK and AKT.

Conclusion: Our findings show that BAF312 has significant anticancer effects in EOC cells by inhibiting the ERK and AKT pathways, and might potentially be used to treat EOCs.

Background/aim: Low selectivity and high frequency of side-effects are the major problems of currently used chemotherapeutics. Among natural compounds, the polyprenylated acylphloroglucinol, guttiferone E, isolated from Brazilian red propolis, has attracted attention due to its marked anticancer properties and was evaluated here for its role against osimertinib-resistant H1975 cells (with double mutations of epidermal growth factor receptor: EGFR L858R/T790M).

Materials and methods: Guttiferone E was obtained from red propolis using established extraction procedures. Guttiferone E was tested using the H1975 cell line in in vitro (2D and 3D) cell cultures and in vivo in BALB/c athymic nude mice. Live/dead assay was also performed to support the results. Tumor tissues obtained from in vivo studies were used for western blotting. Guttiferone E reduced H1975 cell viability in a concentration-dependent manner. The IC₅₀ values in 2D and 3D cell lines were 2.56±0.12 μM and 11.25±0.34 μM. Furthermore, at 10 mg/kg intraperitoneally, guttiferone E significantly reduced the tumor volume in tumor xenografts when used alone and in combination with carboplatin. Guttiferone E and carboplatin displayed synergistic inhibition of H1975 cells and animal tumors. Co-treatment of guttiferone E with carboplatin induced more prominent apoptosis than treatment with either drug alone. Guttiferone E treatment induced cleavage of poly-ADP ribose polymerase and induced apoptosis by significantly reducing levels of mammalian target of rapamycin, sirtuin 1, sirtuin 7, superoxide dismutase, programmed death-ligand 1, and programmed cell death 1 in tumor tissues.

Conclusion: Our results show guttiferone E to be a promising, novel and potent antitumor drug candidate for osimertinib-resistant lung cancer with EGFR L858R/T790M mutations.

Background/aim: Breast cancer is a heterogeneous disease with many subtypes, and the association between these subtypes and exposure to environmental factors such as radiation remains controversial. Although the rat is used widely for research into human breast cancer, the heterogeneity and subtype definitions are unclear. Here, we leveraged an archive of rat mammary cancer samples and gene expression microarray data to classify tumors and examine their association with exposures.

Materials and methods: Eighty-four mammary cancer and 12 normal mammary tissue samples were obtained from previous experiments in which rats were exposed to different types of radiation, chemical carcinogens, and diets. Tumors were then subjected to immunohistochemical (IHC) analysis of conventional biomarkers, as well as gene expression profiling; they were then classified by three approaches based on IHC results, the PAM50 classifier algorithm, and unsupervised clustering of gene expression profiles.

Results: IHC identified four subtypes (luminal A-like, luminal B-like 1, luminal B-like 2, and triple-negative), while PAM50 identified six (luminal A, luminal B, basal-like, HER2-enriched, normal-like, and claudin-low). Unsupervised clustering divided the tumors into three large, statistically significant, groups (named "luminal A", "luminal B", and "non-luminal" clusters). The results of the three approaches were significantly associated with each other. Exposure to radiation and chemical carcinogens during post-pubertal development was significantly associated with an increased risk of developing luminal A tumors, whereas exposure to a high corn-oil diet was associated with a higher likelihood of luminal B tumors.

Conclusion: Rat mammary cancer subtypes resemble those in humans and are related to environmental factors.

Background/aim: Methyl gallate (MG), a plant phenolic compound, has known anticancer properties. However, its effects on canine mammary gland tumors (CMTs) are unclear. This study evaluated the impact of MG on cell viability, migration, and apoptosis in two CMT cell lines.

Materials and methods: CMT-U27 and CF41.mg cells were used. In vitro experiments included MTT and scratch assays, Annexin-V/propidium iodide double staining, immunocytochemistry, and western blot analyses. An in vivo CMT xenograft mouse model was also used to observe the effects of MG on tumor growth and vasculature. Immunohistochemistry was performed to analyze vessel density and apoptosis in tumor tissues. Cell migration and tube formation assays with canine aortic endothelial cells assessed the anti-angiogenic effects of MG.

Results: Data showed a significant decrease in cell viability and migration in both CMT cell lines after 24 h exposure to various MG concentrations. MG treatment induced dose-dependent apoptotic cell death and elevated cleaved caspase-3 expression. In vivo experiments confirmed tumor growth suppression 21 days post-treatment with 40 mg/kg MG. Tumor tissues displayed increased cleaved caspase-3 and reduced vessel density. MG also inhibited cell migration and disrupted tube formation in canine endothelial cells.

Conclusion: MG has potential as an anticancer drug for CMTs by promoting apoptotic cell death and reducing angiogenesis, highlighting its therapeutic promise.

Background/aim: Durvalumab consolidation is less effective in patients with epidermal growth factor receptor mutant (EGFR M+) NSCLC. Studies of durvalumab on EGFR M+ NSCLC as an expression of programmed death-ligand 1 (PD-L1) expression are limited. The purpose of this study was to determine the effect of durvalumab on PD-L1 expression in EGFR M+ patients.

Patients and methods: This study included 249 unresectable stage III NSCLC patients treated with durvalumab. The primary outcome was progression-free survival (PFS). Cox multivariate analysis was performed based on EGFR and PD-L1 statuses: EGFR M-, PD-L1 ≥50% (cohort A); EGFR M-, PD-L1 <50% (cohort B); EGFR M+, PD-L1 ≥50% (cohort C); and EGFR M+, PD-L1 <50% (cohort D).

Results: Overall, 31 of 249 (12.4%) and 218 of the 249 (87.6%) patients had EGFR M+ and EGFR M- NSCLC, respectively. Median PFSs and OSs did not differ (PFS: 16.6 vs. 18.7 months, p=0.591; OS: 37.4 vs. 35.7 months, p=0.271). Median PFS of cohort A did not significantly differ from the median PFSs of cohorts B and C, but it was significantly longer than the median PFS of cohort D (23.7 vs. 15.2 months, p=0.045). Cox multivariate analysis revealed that cohort D exhibited a worse PFS (adjusted hazard ratio=2.27, 95% confidence interval=1.11-4.66, p=0.025) compared with cohort A. Median OSs were not different between the four cohorts.

Conclusion: Durvalumab consolidation provided similar benefit in EGFR M+ patients with PD-L1 ≥50% compared with EGFR M- patients. A therapeutic role of durvalumab in patients with EGFR M+, high PD-L1 unresectable stage III NSCLC should be considered.

Background/aim: The objective of this research was to assess the frequency and intensity of radiation-induced esophagitis in breast cancer patients treated with supraclavicular radiotherapy field irradiation.

Patients and methods: This study involved 100 patients with positive lymph nodes receiving radiotherapy to the breast or chest wall along with supraclavicular field irradiation, with toxicity levels assessed weekly. Treatment utilized the 3D conformal technique, and variables, such as mean and maximum dose to the cervical esophagus, mean dose to the entire esophagus, and length of the esophagus within the treated area were recorded.

Results: The occurrence of grade 2 or higher esophagitis was 48%, with patients facing the risk of developing such esophagitis at an average dose of 13 Gy. The probability of grade 2 esophagitis occurring at doses exceeding 13 Gy was statistically significantly higher (p<0.001) with an odds ratio of 24.4.

Conclusion: Limiting the mean cervical esophagus dose to <13 Gy could help reduce the frequency and severity of grade 2 or higher toxicity.

Background/aim: Ovarian cancer (OC) is a leading cause of cancer-related mortality among women, and there remains a significant unmet need for new therapeutic agents to improve patient outcomes. This study aimed to explore drug repositioning by screening a library of Food and Drug Administration (FDA)-approved compounds to identify those with therapeutic potential against OC. We also aimed to elucidate the molecular mechanisms of action of such compounds to better understand how they inhibit cancer cell proliferation.

Materials and methods: Using the WST-1 assay, a library of 1710 FDA-approved drugs was screened to evaluate their effects on OC cell proliferation. The molecular mechanisms underlying the effects of selected compounds were assessed through terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblot analysis.

Results: Screening of FDA-approved libraries revealed valrubicin as a potent inhibitor of OVCAR8 cell proliferation and SKOV3 and A2780 cell growth. Furthermore, valrubicin treatment led to increased DNA fragmentation, as evidenced by the TUNEL assay, and activated apoptosis signaling through enhancement of cleaved caspase-3 and poly(ADP-ribose) polymerase levels.

Conclusion: Valrubicin, through drug repositioning, can be applied as a new therapeutic agent for OC.

Background/aim: The interest in phytotherapy in patients with cancer is immensely high. When using herbal medicine, knowledge of potential side-effects is essential as part of counselling the patient. The aim of this study was therefore to collect information on the side-effects of popular medicinal plants and to compare different official and the most popular sources of information reporting the side-effects of phytotherapeutics.

Materials and methods: Four different databases were reviewed from 09 February 2021 to 01 March 2022. These were the German monographs of the German Federal Institute for Drugs and Medical Devices, the European monographs of the European Medicines Agency, the website About Herbs (https://www.mskcc.org/cancer-care/diagnosis-treatment/symptom-management/integrative-medicine/herbs) and the German Red List. A total of 171 medicinal plants were chosen from the German monographs. These plants were relevant for supportive cancer treatment, targeting symptoms e.g. pain, nausea, vomiting, mucositis or fatigue.

Results: Out of the 171 selected plants, only 20 were found in all four sources. The compilation of the data showed there to be a huge disparity in the number of plants listed by each database and the type and frequency of the side-effects described. The reasons for this are manifold: Lack of interest, different interest groups, different origins (Europe versus America) and no standardized terminology.

Conclusion: Physicians should not rely exclusively on one source to inform themselves about potential side-effects of phytotherapeutics but should use several sources to ensure the best possible safety of the patient. Since there seems to be too few data on certain medicinal plants for which no side-effects have been documented, more clinical studies are needed.