Human Cancer Research Articles

Introduction Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer to treat because it lacks the expression of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2). A significant majority of deaths related to cancer are caused by tumor metastasis and angiogenesis. Vascular endothelial growth factor receptor 2 (VEGFR2) plays a significant role in angiogenesis. Instead of developing new molecules, drug repurposing, also known as repositioning, seeks innovative uses for outdated drugs or those that fail due to ineffectiveness. Methods In this study, we performed high-throughput virtual screening of FDA approved drug library taken from Enamine bioactive collection targeting VEGFR proteins, and the top hit compounds analyzed by molecular dynamics simulations and MM-GBSA were considered for further in vitro analyses against human breast cancer cells, MDA-MB-231 and MDA-MB-468 cells followed by in ovo assay using the Chorioallantoic Membrane (CAM) model. Results The results revealed that risperidone was effective against triple-negative breast cancer, with IC50 values ranging from 46.53 to 49.76 µM. The findings of our study demonstrated that risperidone, an antipsychotic drug, could successfully inhibit human breast cancer cells in silico, in vitro and in ovo . Discussion We could prove that a structure-based drug repurposing approach is an effective strategy to produce a promising antiangiogenic repurposed drug that could also inhibit VEGFR2 in breast cancer. Although risperidone showed modest potency, its clinical availability and repurposing potential support further evaluation in preclinical and clinical settings.

The most widely used cell line for studying ductal carcinoma in situ (DCIS) premalignancy is the transformed breast epithelial cell line, MCF10DCIS.com. During its original clonal isolation and selection, MCF10DCIS.com acquired a heterozygous M452I mutation in the proprotein convertase PCSK5, which has never been reported in any human cancer. The mutation is noteworthy because PCSK5 matures GDF11, a TGFβ-superfamily ligand that suppresses progression of triple-negative breast cancer. We asked here whether PCSK5M452I and its activity toward GDF11 might contribute to the unique properties of MCF10DCIS.com. Using an optimized in-cell GDF11 maturation assay, we found that overexpressed PCSK5M452I was measurably active but at a fraction of the wildtype enzyme. In a PCSK5-/- clone of MCF10DCIS.com reconstituted with different PCSK5 alleles, PCSK5M452I was mildly defective in anterograde transport. However, the multicellular organization of PCSK5M452I addback cells in 3D matrigel cultures was significantly less circumscribed than wildtype and indistinguishable from a PCSK5T288P null allele. Growth of intraductal MCF10DCIS.com xenografts was similarly impaired along with the frequency of comedo necrosis and stromal activation. In no setting did PCSK5M452I exhibit gain-of-function activity, leading us to conclude that it is hypomorphic and thus compensated by the remaining wildtype allele in MCF10DCIS.com. Implications: This work reassures that an exotic PCSK5 mutation is not responsible for the salient characteristics of the MCF10DCIS.com cell line.

Tyrosine kinase inhibitors (TKIs), targeted therapeutic agents, have significantly improved survival outcomes in patients with chronic myeloid leukemia (CML). However, the emergence of drug resistance remains a challenge, with the underlying mechanisms still largely unknown. Deubiquitinating enzymes (DUBs) have been reported as potential targets in many human cancers. In this study, we identified ubiquitin-specific protease 8 (USP8) as a potential prognostic target for CML drug resistance through bioinformatics analysis and validation in clinical samples. Functionally, knockdown of USP8 inhibited proliferation and increased apoptosis and TKI sensitivity in various CML cell lines. Mechanistically, immunoprecipitation-mass spectrometry analysis and molecular docking demonstrated an interaction between USP8 and eukaryotic translation initiation factor 2 subunit alpha (EIF2S1). USP8 stabilizes EIF2S1 protein by inhibiting its K48-linked ubiquitination, thereby preventing its degradation via the proteasome pathway. In other words, USP8 knockdown suppressed EIF2S1 protein expression and inhibited tumor growth both in vitro and in vivo, further suppressing TKI resistance. In summary, our results suggest that USP8 is overexpressed in CML and linked to resistance to TKIs. We have unveiled a previously unknown mechanism of CML drug resistance, which may provide novel perspectives on the advancement of targeted therapeutic strategies and clinical interventions.

Background/AimCross-talk between forkhead box O1 (FOXO1), a transcriptional factor known to function as a tumor suppressor via the PI3K/AKT pathway, and glucocorticoid receptor (GR) has been implied in non-urothelial cells. The present study aimed to investigate the association of FOXO1 and GR expression in bladder cancer and its prognostic significance.Materials and MethodsImmunohistochemical staining for GR, FOXO1, and p-FOXO1 (a phosphorylated/inactivated form) was performed in a set of bladder cancer tissue microarray comprising 50 low-grade non-invasive tumors, 28 high-grade non-muscle-invasive tumors, and 51 high-grade muscle-invasive tumors. Western blotting for FOXO1 and p-FOXO1 was also conducted in human bladder cancer cells.ResultsGR expression was detected in 109 [84.5%; 39 (30.2%) weakly positive (1+), 39 (30.2%) moderately positive (2+), 31 (24.0%) strongly positive (3+)] tumors, whereas FOXO1 and p-FOXO1 were immunoreactive in 17 [13.2%; 16 (12.4%) 1+, 1 (0.8%) 2+] and 71 [55.0%; 57 (44.2%) 1+, 14 (10.9%) 2+] tumors, respectively. The expression levels of GR were positively and negatively correlated with those of FOXO1 (p=0.003) and p-FOXO1 (p=0.009), respectively. GR(0/1+)/FOXO1(0) and GR(0/1+)/p-FOXO1(1+/2+) were significantly more often observed in high-grade (vs. low-grade) or muscle-invasive (vs. non-muscle-invasive) tumors. Both univariate and multivariate analyses revealed that GR(0/1+)/FOXO1(0) and GR(0/1+)/p-FOXO1(1+/2+) were associated with a significantly higher risk for the recurrence of non-invasive disease or progression of muscle-invasive disease. In 2 GR-positive bladder cancer lines, glucocorticoids (i.e., dexamethasone, prednisone) and a GR antagonist (i.e., RU486) induced the levels of FOXO1 and p-FOXO1 expression, respectively.ConclusionThe expression levels of GR and FOXO1 or p-FOXO1 were strongly correlated in bladder cancer. Specific GR/FOXO1 and GR/p-FOXO1 expression profiles served as independent predictors of disease recurrence or progression.

Colorectal cancer (CRC) continues to pose substantial clinical challenges owing to the limited response and emergent resistance to standard chemotherapeutic regimens, including FOLFOX. The present investigation explored the antitumor efficacy of JI-CJ002, a standardized herbal formula consisting of Angelica gigas, Aconitum carmichaeli, and Zingiber officinale (2:1:3 ratio), and its combined effects with FOLFOX in in vitro settings. Cytotoxic activities were assessed in HT29 and HCT116 human colorectal cancer cell lines by conducting MTT assays, Annexin V/7-AAD staining, and western blotting. Network pharmacology techniques were employed to identify common targets among JI-CJ002, FOLFOX, and CRC-associated gene profiles. JI-CJ002 exhibited broad-spectrum cytotoxicity that was both time- and dose-dependent in HT29 and HCT116 cell lines. Network analysis identified 89 common targets predominantly involved in DNA repair, apoptosis, and chemoresistance pathways. The combination treatment led to a significant, synergistic reduction in cell viability and elevated apoptotic markers, including Annexin V/7-AAD positivity and cleaved PARP. Mechanistically, co-treatment inhibited ATM, ATR, p-CHK1, p-CHK2, p-Cdc2, and p-p53, while sustaining γ-H2AX accumulation, signifying persistent DNA damage and inadequate activation of cell cycle arrest checkpoints. Immunofluorescence revealed a further increase in γ-H2AX nuclear foci. JI-CJ002 augments the therapeutic effect of FOLFOX by suppressing DNA damage response and inducing aberrant cell cycle progression, thereby supporting its development as a chemo-sensitizing agent for colorectal cancer therapy.

Tumor hypoxia induced alterations in the epigenetic landscape and alternative splicing influence cellular adaptations. PRMT5 is a type II protein arginine methyltransferase that regulates several tumorigenic events in many cancer types. However, the regulation of PRMT5 and its direct implication on aberrant alternative splicing under hypoxia remains unexplored. In this study, we observed hypoxia-induced upregulation of PRMT5 via the CTCF in human breast cancer cells. Further, PRMT5-mediated symmetric arginine dimethylation H4R3me2s and H3R8me2s directly regulated the alternative splicing of TCF3. Under hypoxia, PRMT5-mediated histone dimethylation at the intronic conserved region (ICR) present between TCF3 exon 18a and exon 18b recruits DNMT3A, resulting in DNA methylation. DNA methylation at the TCF3-ICR is recognized and bound by MeCP2 resulting in RNA-Pol II pausing, promoting the recruitment of the negative splicing factor PTBP1 to the splicing locus of TCF3 pre-mRNA. PTBP1 promotes the exclusion of exon 18a which results in the production of the pro-invasive TCF3-18B (E47) isoform which promotes EMT and invasion of breast cancer cells under hypoxia. Collectively, our results indicate PRMT5-mediated symmetric arginine dimethylation of histones regulates alternative splicing of TCF3 gene thereby enhancing EMT and invasion in breast cancer hypoxia.

Combination of B-AP15 and HSP90 inhibitor tanespimycin induces ROS-mediated cytotoxicity in human lung cancer cells

Tumor hypoxia induced alterations in the epigenetic landscape and alternative splicing influence cellular adaptations. PRMT5 is a type II protein arginine methyltransferase that regulates several tumorigenic events in many cancer types. However, the regulation of PRMT5 and its direct implication on aberrant alternative splicing under hypoxia remains unexplored. In this study, we observed hypoxia-induced upregulation of PRMT5 via the CTCF in human breast cancer cells. Further, PRMT5-mediated symmetric arginine dimethylation H4R3me2s and H3R8me2s directly regulated the alternative splicing of TCF3. Under hypoxia, PRMT5-mediated histone dimethylation at the intronic conserved region (ICR) present between TCF3 exon 18a and exon 18b recruits DNMT3A, resulting in DNA methylation. DNA methylation at the TCF3-ICR is recognized and bound by MeCP2 resulting in RNA-Pol II pausing, promoting the recruitment of the negative splicing factor PTBP1 to the splicing locus of TCF3 pre-mRNA. PTBP1 promotes the exclusion of exon 18a which results in the production of the pro-invasive TCF3-18B (E47) isoform which promotes EMT and invasion of breast cancer cells under hypoxia. Collectively, our results indicate PRMT5-mediated symmetric arginine dimethylation of histones regulates alternative splicing of TCF3 gene thereby enhancing EMT and invasion in breast cancer hypoxia.

The direct use of chemotherapeutic agents in gastric cancer treatment can result in systemic adverse effects and inadequate therapeutic efficacy. The superior features of nanoparticles provide them with potent tools for enhancing the targeted delivery of chemotherapeutic agents. Herein, we developed the fabrication of a DT&IG@ZIF-8@CC-PG nano-carrier, which was paired with photothermal therapy (PTT) and calcium overload to provide synergic therapeutic effects. The drug carrier comprised a zeolite imidazolate (ZIF-8) core and a PEG-altered calcium carbonate (CC) shell. The core was a co-loading site for the chemotherapeutic drugs docetaxel (DT) and the photosensitizer indocyanine green (IG). Comparative in vitro cellular studies showed that the toxicity of DT&IG@ZIF-8@CC-PG against HGT-1 human gastric cancer cells was remarkably greater than that of single chemotherapy. This can be attributed to chemotherapy, PTT, and calcium overloading. The apoptotic mode of HGT-1 cell death was confirmed by acridine orange/propidium iodide and Annexin V-FITC/PI staining methods, and the results revealed that DT&IG@ZIF-8@CC-PG effectively induces apoptosis. This drug-laden nano-carrier exhibits remarkable properties, including excellent stability, increased drug loading, and effective drug release, providing a promising opportunity for synergistic treatment.

In vivo models that replicate and reproduce human lung cancer and its response to therapy are necessary for the development of new therapeutic strategies and understanding drug resistance. Imaging lung tumors in live animals to monitor tumor growth and response to therapy is challenging due to the location of the lungs and their constant movement during breathing. X-ray velocimetry (XV) is a novel functional lung imaging technique that maps regional lung expansion during breathing, providing spatial information on where ventilation changes occur. The aim of this pilot study was to use XV and flexiVent lung mechanics assessments to determine the effect of tumor growth on lung function in mice at 2- or 3-weeks post tumor induction, and to evaluate the efficacy of these two tools. Histological analysis showed that tumour growth was not uniform between animals. At 3-weeks post tumor induction, some XV ventilation and flexiVent lung mechanics parameters were significantly different from baseline. Both techniques gave metrics which correlated with the tumour counts from the histology. In some mice XV revealed localised regions with altered expansion rates.

Cancer genes, including oncogenes and tumor suppressor genes, are crucial subjects of study in human health. With advancements in nonhuman primate genome research, recent investigations have started to explore the relationship between human cancer genes and various primate species, implying possible links between cancer genes and nonhuman primate species. However, these findings are commonly limited to only a few primate species. Here, we investigate the distribution of 726 human cancer genes across 31 nonhuman primate species and 4 nonprimate species, comparing them with a randomly selected set of 339 other human genes. Overall, a higher ratio of cancer genes was found to have emerged before primate speciation compared with random human genes; however, this trend did not necessarily continue after primate speciation. Furthermore, our investigation into primate clades suggests that the absence of certain cancer genes in a clade may reflect recent emergence in other clades in which they exist, rather than elimination within the clades in which they are absent.

Gene expression and regulation with or without alternative splicing are crucial for tissues and cells to function correctly. They have been studied from three almost independent perspectives at the genome level: 1- Recognition of splicing quantitative trait loci (sQTLs), 2- Expression quantitative trait loci (eQTLs) recognition, and 3- Recognition of longer-range physical chromatin interactions between genome segments which model 3D dynamics of cells and tissues. Even though the associations between eQTLs and longer-range chromatin interactions have been previously studied, a similar relationship between sQTLs and chromatin interactions has yet to be analyzed. In this case, examining whether sQTLs control the alternative splicing of their target genes’ mRNA via physically interacting genome segments is crucial. We have jointly analyzed high-throughput chromatin conformation capture (Hi-C) and sQTL datasets over eight human cancer tissues. We have discovered a positive association between the number of genes having sQTLs and chromatin interaction frequency. Such a positive association still exists when we also control for eQTLs. Additionally, sQTLs and their target genes generally exist inside identical topologically associating domains (TADs). These findings are observed over the whole set of analyzed cancer types and functional subsets of the sQTL dataset, such as survival-related sQTLs. Furthermore, tissue-specific sQTLs are statistically enriched in tissue-specific frequently interacting regions (FIREs) in 6 out of 8 human cancer tissues (Chronic Myeloid Leukemia, Colon Adenocarcinoma, Acute Myeloid Leukemia, Lung Adenocarcinoma, Prostate Cancer, Sarcoma). Our sQTL and Hi-C datasets have shown the existence of closer spatial distance between sQTLs and their target genes with possible alternative splicing across several different cancer types in humans. Such a closer spatial distance also exists, independent of whether we integrate eQTLs into the analysis. We found that sQTLs regulate alternative splicing through chromatin interactions. Source code of the analysis in this research is available on https://github.com/seferlab/sqtlhic .

Companion animals develop spontaneous tumors with biological and immunological features closely resembling human cancers. The tumor microenvironment (TME), particularly its immune infiltrates, plays a pivotal role in tumor progression and immune evasion. This review summarizes current knowledge on the composition and function of immune cells (including T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells) in the TME of canine and feline tumors. A better understanding of these mechanisms may aid in identifying prognostic biomarkers and novel immunotherapeutic targets in both veterinary and human oncology.

Colorectal cancer (CRC) is a complex multifactorial disease caused by genetic and epigenetic changes playing a vital role in its development and progression. Chemotherapy remains a major option in the treatment of CRC. However, due to its unintended effects on normal tissue, research on identifying plant-based therapeutic agents as an alternative treatment modality has gained attention. Fisetin, a plant-derived flavonoid, has shown promising effects as an anticancer agent against several human cancers, including colon cancer. However, there is limited research focusing on studying the mechanism of action of fisetin. The PI3K/AKT/mTOR pathway as a key regulator of cancer cells has become a promising target for potential anti-cancer development. This study examined the anti-cancer effects of fisetin, emphasizing its effects on the PI3K/AKT/mTOR and apoptosis pathways in human colon cancer Caco-2 cells. The Caco-2 cells were treated with different concentrations (15, 30, 60, 90, or 120 µM) of fisetin for 12 or 24 h. Cell viability was evaluated using the MTT assay, while the expressions of PI3K/AKT/mTOR pathway genes and apoptosis genes, BAX and BCL-2, were analyzed by qRT-PCR. Fisetin markedly decreased the cell viability in a dose- and time-dependent manner. Fisetin down-regulated BCL-2, PI3K, mTOR, and NF-κB gene expression while up-regulating BAX gene expression. This suggested the inhibition of PI3K/AKT/mTOR pathway and induction of apoptosis. GeneMANIA and OncoDB further corroborated these results. These data demonstrate that the antiproliferative effects of fisetin were medicated through the modulation of PI3K/AKT/mTOR and apoptosis pathway. Thus, the study underscores fisetin’s potential as a cancer-preventative drug against cancer.

The Journal retracts the article "Synergistic Effect of Bioactive Anticarcinogens from Soybean on Anti-Proliferative Activity in MDA-MB-231 and MCF-7 Human Breast Cancer Cells In Vitro" [...].

In this work, the synthesis and characterization of quinolime-1,2,3-triazoles (7a-n) via azocoupling, O-propargylation and copper(I) catalyzed azide alkyne cycloaddition reactions is reported. All the synthesized compounds were evaluated for in vitro anticancer activity against human breast cancer cell lines like MDA-MB-468, MDA-MB-231 and MCF-7 and 5-fluorouracil (5-FU) as reference drug. Among all, only five compounds 7d, 7j, 7k, 7l and 7n exhibited greater activity than the standard drug 5-fluorouracil against three breast cancer cell lines with IC50 values ranging from 1.1 µM to 9.3 µM. Similarly, in vitro tyrosine kinase EGFR inhibition for the same compounds revealed that compound 7l has exhibited 2.6 times more inhibitory activity with IC50 value of 0.15 µM compared to erlotinib. Finally, in silico molecular docking on EGFR shown good binding interactions with target protein (pdb id 4HJO).

The novel series of 3-acetyl phenylthiazolidine-4-carboxyamide derivatives were prepared, structurally characterized by FTIR, 1H and 13C-NMR, and mass spectrometry, and described for their possible applications against prostate cancer cells. These amide thiazolidines include many substituents on a phenyl ring, such as 3-NO2, 3,4,5-tri-OCH3, 4-COCH3, 3,4-di-OCH3, benzoyl, and diphenyl. Biological activity assays applying the MTT assay for PC3 cells were shown to evaluate the bioactivity of these thiazolidines. The amide thiazolidines revealed promising cytotoxic amide thiazolidines TAM1 (IC50 = 75.95 µg/ml) and TAM2 (IC50 = 79.82 µg/ml) displayed notable strength against PC3 cells. The molecular docking against DNA gyrase, two types of proteins (1SJO and 4HJO), and enzymes exposed strong binding interactions of an examined molecule inside their active sites, making them valuable applicants for further development as therapeutic agents against the human prostate cancer cell line (PC3). Strong total first hyperpolarizability βtot up to 2766.67 a.u. has been achieved for TAM1. The direct correlation was attained between the total hyperpolarizability βtot and Eg (energy gap) and between a βHRS and β//. This study will offer additional knowledge regarding exploring novel thiazolidines, revealing promising, cytotoxic, and nonlinear optical thiazolidines, and progressing in technologies that manipulate and control light for various purposes, such as optical signal processing, photorefractive devices, and photonics.

Correction: Knowledge and attitudes toward human papillomavirus and cervical cancer prevention among women in the Asir Region, Saudi Arabia: a cross-sectional study

Cervical cancer remains a leading cause of morbidity and mortality among women, particularly in low-resource settings where preventive measures are limited. The Papanicolaou (Pap) smear test is recognized as the most effective screening tool for early detection of cervical lesions. This study aimed to assess the prevalence and cytological patterns of cervical abnormalities among Libyan women attending the gynecological outpatient department at the National Oncology Institute, Sabratha, between 2008 and 2012. A total of 669 cervical smears were analyzed and compared with findings from direct visual inspection. The results revealed significant discrepancies between visual examination and Pap smear outcomes, with the latter demonstrating superior sensitivity in identifying inflammatory and premalignant changes. Inflammation was the most common finding, followed by cervical intraepithelial neoplasia (CIN I and II), with higher rates observed among women over 40 years and those with high parity. Despite the known association between human papillomavirus (HPV) and cervical cancer, HPV detection remained low, reflecting limited diagnostic access during the study period. The findings support the implementation of national screening strategies and targeted health education to improve awareness, participation, and early detection. Future research should focus on evaluating specific screening models through prospective studies to optimize cervical cancer prevention across the country.

Psidium cattleianum Sabine (Family Myrtaceae) is a Brazilian native shrub, valued for its diverse health and therapeutic attributes. The current study investigated the phytochemical profile along with the anticancer activities of the n-hexane extract (HE) of P. cattleianum aerial parts and its subfractions. GC-MS and HPTLC-MS were used for phytochemical analysis. The human breast adenocarcinoma cells (MCF-7) and the human colon cancer cells (HCT-116) were used to investigate the anticancer effect in the viability, migration, and clonogenic assays. The GC-MS analysis of HE identified thirty-two components categorized mainly into terpenes, hydrocarbons, and sterols. β-caryophyllene oxide (12.07%) and humulene (7.42%) were the most abundant oxygenated and non-oxygenated metabolites, respectively. Concerning HE’s subfractions, fraction I is prolific with caryophyllene oxide (19.48%) and humulene (9.96%), while fraction II was rich in caryophyllene oxide (6.89%). HPTLC-MS analysis of fractions III-V identified the presence of nonadecatetraene, heptacosanol, and dihydroxy-oxo-ursenoic acid in fraction III; caryophyllene and littordial C in fraction IV, while guavanoic acid, p-coumaroyl caffeoylquinic acid, cholestane heptol, tocopherol, heptacosanedione, and trans-calamenene in fraction V. Concerning the anticancer results, the HE showed potent cytotoxicity with IC50 29.18 ± 0.43 μg/mL (MCF-7) and 56.55 ± 6.8 μg/mL (HCT-116). In addition, at maximum tested doses approximating ½ IC50 (15 and 28 μg/mL) in cytotoxicity assay, it displayed significant percent wound closure of 22.78 ± 2.13% and 12.76 ± 1.88%, respectively. While at doses corresponding to ¼ IC50 (7.5 and 14 μg/mL), the HE displayed a colony formation efficiency of 2% and 0% on MCF-7 and HCT-116, respectively. Subfractions I and II, rich in caryophyllane sesquiterpenes, such as caryophyllene oxide, showed the best activity in all assays. Molecular docking of β-caryophyllene oxide, as the most identified bioactive metabolite, revealed an energetically favorable binding pose driven through hydrophobic interactions at the estrogen receptor ligand binding domain. The study endorses P. cattleianum HE and its selected fractions in the control of breast and colon cancers; however, further investigation into an appropriate in vivo model is required.