Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.
- MeSH
- azoxymethan toxicita MeSH
- chronická nemoc MeSH
- indoly farmakologie terapeutické užití MeSH
- kolitida farmakoterapie chemicky indukované metabolismus patologie MeSH
- kolorektální nádory * farmakoterapie metabolismus patologie MeSH
- modely nemocí na zvířatech * MeSH
- molekulární mimikry MeSH
- myši inbrední C57BL * MeSH
- myši MeSH
- nádory asociované s kolitidou patologie farmakoterapie metabolismus MeSH
- síran dextranu toxicita MeSH
- zánět farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: The presence of MYC and BCL2 translocations (ie, double-hit lymphoma, DHL) in large B-cell lymphoma (LBCL) is associated with reduced chemosensitivity, but less is known on its impact on radiotherapy (RT) efficacy. METHODS AND MATERIALS: Patients with LBCL who received their first course of RT for relapsed/refractory disease between 2008 and 2020 were eligible if there was adequate pathologic evaluation to be categorized as DHL versus non-DHL as per the World Health Organization (fifth edition). Separate analyses were conducted by treatment intent. Predictors for response (complete and partial) and local recurrence (LR) were evaluated using Cox regression analysis. LR analysis was restricted to curative-intent patients to ensure adequate follow-up. RESULTS: Three hundred and eighty-three patients (102 DHL, 281 non-DHL, and 44% curative) were treated at 447 sites. Median time from diagnosis to RT was 11.6 months, with 38.7% of patients having primary chemorefractory disease, 37.4% having received >2 lines of systemic therapy, and 24% status post-stem cell transplant. Median biological equivalent dose (alpha/beta: 10) was 28 Gy (range: 3.2-60.0) for palliative and 46.9 Gy (range: 6.4-84.0) for curative-intent patients. With a median follow-up of 41.1 and 41.5 months among curative and palliative patients, respectively, the response was high (81.1% curative, 60.1% palliative). On univariate analysis, DHL pathology was not associated with RT response in either curative or palliative patients. Among curative patients, 2-year LR rate was 38.8%. On multivariable analysis, DHL pathology was associated with a 2 times higher risk of LR (95% CI: 1.05-3.67, P = .03), with a crude LR rate of 42.9% (DHL) versus 28.9% (non-DHL). RT was well tolerated with low rates of grade 3 or higher acute toxicity (1.8% curative, 2.9% palliative). CONCLUSIONS: Relapsed/refractory LBCL remains radioresponsive with a 60%-80% response rate to RT. Although DHL pathology does not appear to influence RT response, its presence is associated with higher rates of LR, suggesting that it may be more radioresistant.
- MeSH
- difúzní velkobuněčný B-lymfom * radioterapie patologie genetika MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru * patologie MeSH
- mladý dospělý MeSH
- protoonkogenní proteiny c-bcl-2 genetika MeSH
- protoonkogenní proteiny c-myc genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- translokace genetická MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Intracellular delivery is a bottleneck in the development of therapeutic peptides and proteins. Here, we demonstrate the efficient delivery of omoMYC, the first MYC inhibitor in clinical trials, using HBpep-SP, an engineered peptide forming liquid-liquid phase-separated coacervates. HBpep-SP coacervates facilitate efficient cellular uptake and intracellular delivery of the omoMYC peptide at concentrations lower than those required for spontaneous uptake. Strikingly, omoMYC coacervates result in reduced proliferation and apoptosis induction in the low c-MYC expressing cell lines HEK293 and SH-SY5Y cells, but not in HeLa and SK-N-BE(2) cells with high c-MYC/MYCN expression, respectively, suggesting that endogenous MYC/N levels may impact the effects of omoMYC. Importantly, our approach bypasses the need for cell penetration-enhancing chemical modifications, offering a novel strategy for the investigation of peptide drug mechanisms in therapeutic development.
- MeSH
- apoptóza účinky léků MeSH
- HEK293 buňky MeSH
- HeLa buňky MeSH
- lékové transportní systémy metody MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- peptidy * chemie MeSH
- proliferace buněk účinky léků MeSH
- protoonkogenní proteiny c-myc * antagonisté a inhibitory metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Previous research indicated that the cytotoxic activity of the antitumor platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (56MESS) was not primarily attributed to DNA binding, despite the complex being confirmed to localize also in the nucleus. In this study, we have demonstrated that the antiproliferative activity of 56MESS indeed involves DNA binding. Furthermore, in addition to binding duplex DNA, the complex also interacts with non-canonical secondary DNA structures, such as G-quadruplexes (G4s) and i-Motifs (iMs). This interaction leads to the suppression of G-regulated oncogene expression and disrupts key enzymatic processes associated with DNA, potentially contributing to DNA damage and the biological activity of 56MESS. These findings build upon previously published results, revealing that the anticancer activity of 56MESS is significantly more multifaceted than previously understood, involving multiple distinct mechanisms.
- MeSH
- DNA metabolismus chemie MeSH
- down regulace * účinky léků MeSH
- G-kvadruplexy * účinky léků MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny * farmakologie chemie MeSH
- poškození DNA * účinky léků MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemie MeSH
- protoonkogenní proteiny c-myc * genetika metabolismus MeSH
- protoonkogenní proteiny p21(ras) * genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The hedgehog signaling pathway plays an important role in vertebrate embryonic development, tissue homeostasis, and tumorigenesis. Constitutive activation of Hh signaling in various human tumors leads to GLI-mediated transcription and tumor progression. Based on the preliminary screening of a large library of known triterpenes that exhibited interesting Hh inhibitory activity, we designed and synthesized a new series of triterpenoid analogues containing aromatic heterocyclic substituents at position C-2 to enhance their interference with Hh signaling. In this study, we evaluated the effect of 15 synthesized triterpenoids on cell proliferation and Hh pathway activity in relevant cancer cell lines. Among these compounds, two derivatives, 11a and 11b, both featuring a furan ring at position C-2, demonstrated potent inhibitory effects on proliferation and induced cell death in nonsmall cell lung cancer (NSCLC) and prostate cancer cell lines exhibiting hyper-activated Hh signaling. Moreover, these compounds significantly reduced GLI-mediated transcription in cell-based reporter assays. Detailed immunoblot analyses revealed that compounds 11a and 11b decreased the expression of endogenous GLI1 protein and its target genes associated with tumor progression and proliferation, such as Cyclin D1, N-Myc, and Bcl-2, in A549 and DU-145 cancer cells. These findings suggest that the antiproliferative effects of 11a and 11b are mediated through inhibition of the Hh signaling pathway and are promising candidates for the development of new anticancer therapies targeting Hh-dependent tumors.
- Publikační typ
- časopisecké články MeSH
Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs' expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs' expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Early detection of colorectal cancer (CRC) significantly improves its management and patients' survival. Circular RNAs (circRNAs) are peculiar covalently closed transcripts involved in gene expression modulation whose dysregulation has been extensively reported in CRC cells. However, little is known about their alterations in the early phases of colorectal carcinogenesis. METHODS: In this study, we performed an integrative analysis of circRNA profiles in RNA-sequencing (RNA-Seq) data of 96 colorectal cancers, 27 adenomas, and matched adjacent mucosa tissues. We also investigated the levels of cognate linear transcripts and those of regulating RNA-binding proteins (RBPs). Levels of circRNA-interacting microRNAs (miRNAs) were explored by integrating data of small RNA-Seq performed on the same samples. RESULTS: Our results revealed a significant dysregulation of 34 circRNAs (paired adj. p < 0.05), almost exclusively downregulated in tumor tissues and, prevalently, in early disease stages. This downregulation was associated with decreased expression of circRNA host genes and those encoding for RBPs involved in circRNA biogenesis, including NOVA1, RBMS3, and MBNL1. Guilt-by-association analysis showed that dysregulated circRNAs correlated with increased predicted activity of cell proliferation, DNA repair, and c-Myc signaling pathways. Functional analysis showed interactions among dysregulated circRNAs, RBPs, and miRNAs, which were supported by significant correlations among their expression levels. Findings were validated in independent cohorts and public datasets, and the downregulation of circLPAR1(2,3) and circLINC00632(5) was validated by ddPCR. CONCLUSIONS: These results support that multiple altered regulatory mechanisms may contribute to the reduction of circRNA levels that characterize early colorectal carcinogenesis.
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: While the reported incidence of non-tuberculous mycobacterial (NTM) infections is increasing, the true prevalence remains uncertain due to limitations in diagnostics and surveillance. The emergence of rare and novel species underscores the need for characterization to improve surveillance, detection, and management. METHODS: We performed whole-genome sequencing (WGS) and/or targeted deep-sequencing using the Deeplex Myc-TB assay on all NTM isolates collected in Slovakia and the Czech Republic between the years 2019 to 2023 that were unidentifiable at the species level by the routine diagnostic line probe assays (LPA) GenoType CM/AS and NTM-DR. Minimal inhibitory concentrations against amikacin, ciprofloxacin, moxifloxacin, clarithromycin, and linezolid were determined, and clinical data were collected. RESULTS: Twenty-eight cultures from different patients were included, of which 9 (32.1%) met the clinically relevant NTM disease criteria. The majority of those had pulmonary involvement, while two children presented with lymphadenitis. Antimycobacterial resistance rates were low. In total, 15 different NTM species were identified, predominantly rare NTM like M. neoaurum, M. kumamotonense and M. arupense. Notably, clinically relevant M. chimaera variants were also identified with WGS and Deeplex-Myc TB, which, unlike other M. chimaera strains, appeared to be undetectable by LPA assays. Deeplex detected four mixed infections that were missed by WGS analysis. In contrast, WGS identified two novel species, M. celatum and M. branderi, which were not detected by Deeplex-Myc TB. Importantly, one of these novel species strains was associated with clinically relevant pulmonary disease. DISCUSSION: Our study demonstrates the clinical relevance of uncommon NTM and the effectiveness of targeted deep-sequencing combined with WGS in identifying rare and novel NTM species.
- MeSH
- antibakteriální látky * farmakologie MeSH
- atypické mykobakteriální infekce * mikrobiologie diagnóza MeSH
- bakteriální léková rezistence MeSH
- dítě MeSH
- dospělí MeSH
- genotyp MeSH
- klinická relevance MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- mladiství MeSH
- netuberkulózní mykobakterie * účinky léků genetika izolace a purifikace MeSH
- předškolní dítě MeSH
- sekvenování celého genomu * MeSH
- senioři MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
High-grade B-cell lymphomas (HGBCLs) are aggressive blood cancers with a severe disease course, especially when the central nervous system (CNS) is involved. Standard histological examination depends on tissue availability and is currently supplemented with molecular tests, as the status of MYC, BCL2, or BCL6 gene rearrangements is required for proper lymphoma classification. This case report demonstrates the relevance of cerebrospinal fluid (CSF) cell-free DNA testing by integrative next-generation sequencing (NGS) panel. The benefit of this approach resided in tumor genotyping alongside the proof of CNS progression despite MRI negativity, revealing a clonal relationship with the primary tumor lesion. In addition, our strategy allowed us to classify the tumor as DLBCL/HGBL-MYC/BCL2 entity. In clinical practice, such a minimally invasive approach provides a more sensitive tool than standard imaging and cell analyzing techniques, enabling more accurate disease monitoring and relapse prediction in particular cases.
- MeSH
- B-buněčný lymfom genetika patologie diagnóza diagnostické zobrazování MeSH
- cirkulující nádorová DNA genetika MeSH
- difúzní velkobuněčný B-lymfom genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru patologie genetika MeSH
- magnetická rezonanční tomografie * MeSH
- nádorové biomarkery genetika MeSH
- nádory centrálního nervového systému genetika patologie diagnostické zobrazování MeSH
- vysoce účinné nukleotidové sekvenování * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
