PMCID string | Title string | Sentences string |
|---|---|---|
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | In addition, a study revealing the cellular protective impact of α-LA on human bronchial epithelial cells exposed to paraquat through the reduction of ROS and MDA levels confirmed the antioxidant effects of α-LA (41). |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | There is a strong connection between redox regulation and programmed cell death, developmental senescence, and pathogen response. |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | The p53 gene plays a crucial role not just in cancer but also in longevity and aging in humans and mammals (42). |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | Pro-apoptotic Bax and anti-apoptotic Bcl-2 genes are involved in mitochondria-controlled programmed cell death in mammals. |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | The present findings revealed that the expression of p53 and Bax genes in SH-SY5Y cells in the D-gal group was significantly higher than that of the untreated group. |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | However, the expression of the genes was significantly decreased in the α-LA + D-gal and Met + D-gal groups. |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | In addition, Bcl-2 gene expression in the D-gal group decreased significantly compared to the untreated group, while it increased significantly in the α-LA + D-gal and Met + D-gal groups. |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | Literature indicated that there is an upregulation of Bax and p53, as well as a downregulation of Bcl-2 mRNA levels, following the administration of D-gal (434445). |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | Furthermore, according to a study, α-LA further reduced cytochrome c loss in the body by decreasing p53 gene expression and preserving the integrity of the mitochondrial membrane, which reduced apoptosis in older rats (46). |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | However, this study only measured the effect of α-LA on the expression of Bax, Bcl-2, and p53 at the mRNA level, and it is necessary to confirm the effects at the protein level as well. |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | The results showed that α-LA exerted its protective effects by increasing antioxidant capacity and reducing oxidative stress and modulating genes involved in apoptosis, which makes it a promising compound for preventing age-related diseases. |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | H. Nadi Yazdi contributed to writing the original draft, investigation, methodology, and conceptualization; F. Mirzavi contributed to writing the original draft, reviewing, and editing; M. Kazemian Kakhki and A.R. Afshari contributed to methodology and formal analysis; S.H. Mousavi and M. Soukhtanloo contributed to the conceptualization, supervision, and funding acquisition. |
PMC12614211 | The protective effects of α-lipoic acid against D-galactose-induced cellular senescence in human SH-SY5Y neuroblastoma cell line | All authors read and approved the final version of the manuscript. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Neural tumors represent diverse malignancies with distinct molecular profiles and present particular challenges due to the blood-brain barrier, heterogeneous molecular etiology including epigenetic dysregulation, and the affected organ’s critical nature. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | KCC-07, a selective and blood-brain barrier penetrable MBD2 (methyl CpG binding domain protein 2) inhibitor, can suppress tumor development by inducing p53 signaling, proven only in medulloblastoma. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Here we demonstrate KCC-07 treatment’s application to other neural tumors. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | KCC-07 treatment reduced proliferation rates of U-87MG (glioma cell line) and SH-SY5Y (neuroblastoma cell line). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | p53 stabilization occurred in these cell lines without significantly affecting programmed cell death factors under KCC-07 exposure. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Furthermore, tumor cell growth inhibition was enhanced when combined with DNA damaging reagents. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Both phleomycin (radiomimetic agent inducing DNA double strand breaks) and etoposide (topoisomerase II inhibitor inducing DNA double strand breaks) treatment activated p53-dependent signaling for apoptosis and cell cycle arrest, consequently suppressing tumor cell growth. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Dual treatment with KCC-07 (epigenetic modifier) and DNA damaging reagents augmented tumor cell suppression, suggesting greater benefits of combinatorial therapy for neural tumors than previously demonstrated. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The hallmarks of cancer have been updated a couple of times since first proposed by Hanahan and Weinberg in 2000 . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The second generation of cancer hallmarks supplemented 4 additional factors, including ‘genomic instability and mutation’, which can result partly from defective DNA damage repair and DNA damage response (DDR) . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The expanded cancer hallmarks now contain 4 more entities: ‘unlocking phenotype plasticity’, ‘senescent cells’, ‘polymorphic microbiomes’, and ‘nonmutational epigenetic reprogramming’ . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | DNA modification, particularly methylation, is one form of nonmutational epigenetic event, and CpG methylation causes gene silencing . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Several enzymes and proteins are involved in DNA methylation, including DNA methyltransferases (DNMTs), 5’-methylcytosine hydroxylases (TETs), and methyl-CpG binding domain (MBD) proteins . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The MBD protein family consists of eleven proteins including MBD1 to MBD6, which function as DNA methylation readers in gene repression . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Alterations of MBD proteins, particularly MBD1 to MBD4, have been found in several tumors including prostate, endometrial, and brain tumors . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | In particular, MBD2 has functional impacts on hematopoietic and solid tumors. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Reduction or inhibition of MBD2 is advantageous in tumor treatment . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The approach using an MBD2 inhibitor has been studied for the first time, and only so far, in medulloblastoma, the most frequent pediatric brain tumor. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | In medulloblastoma, inhibition of MBD2 binding to methylated DNA by KCC-07, a specific MBD2 inhibitor that is blood-brain barrier penetrable, leads to MDM2 sequestration and p53 stabilization, and eventually suppression of tumor growth in a p53 dependent manner, suggesting that epigenetic modification of DNA could be one of the therapeutic targets for tumor treatment . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Other MBD2 inhibitors including 8, 8-ethylenebistheophylline, CID3100583, APC ([R]-[3-(2-Amino-acetylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester]), and ABA (2-amino-N--acetamide) were suggested as novel candidates, yet the biological effects of these potential MBD2 inhibitors were not verified , which places KCC-07 in a unique position for this purpose. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Another approach to tumor treatment via p53 signaling is by inducing DNA damage, particularly DNA double strand breaks (DSBs), the most deleterious type of DNA damage . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | DSBs are immediately recognized by early responding proteins including ATM (Ataxia telangiectasia mutated), which phosphorylates numerous downstream proteins such as H2AX, KAP1, CHK2, and p53 to trigger appropriate responses to DNA damage. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Chemotherapeutic agents inducing DNA damage activate p53 signaling, leading to cell cycle arrest and programmed cell death to prevent tumor progression [11-14]. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | While targeting epigenetic modification or DNA structure itself is beneficial for tumor treatment, a combinatory effect of KCC-07 and DNA damaging reagents has not been explored. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Here we tested whether the effect of DNA damaging reagents on neural tumor cells can be augmented with KCC-07 exposure. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The results showed additive effects of genotoxic drugs and KCC-07 on tumor cell growth inhibition and programmed cell death, demonstrating the remarkable therapeutic efficacy achieved by combining DNA damage induction and MBD2 inhibition for neural tumor treatment. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Two neural tumor cell lines, U-87MG (originated from malignant glioma, wildtype p53) and SH-SY5Y (a subline of neuroblastoma, wildtype p53), were purchased from the Korean Cell Line Bank (KCLB, Seoul, Korea). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | These cell lines were maintained in Dulbecco’s Modified Eagle Medium (DMEM, high glucose with pyruvate, Gibco, MA, USA) supplemented with 10% Fetal Bovine Serum (FBS, Gibco) and Penicillin-Streptomycin (Gibco) at 37°C with 5% CO2. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | KCC-07 (3-[4-(2-Pyridinyl)-2-thiazolyl]amino]phenol (CAS 315702-75-1)) was obtained from Selleckchem (TX, USA). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Phleomycin (Phleo, CAS 11006-33-0) and etoposide (ETP, CAS 33419-42-0) were purchased from Sigma (MO, USA). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | When necessary, reagents were dissolved in DMSO (dimethyl sulfoxide). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Each experimental condition of drug treatments is indicated in the figures. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Total RNA from cell lines was isolated using TRIzol reagent (Invitrogen/Ambion, TX, USA) according to the manufacturer’s protocol, and cDNA was generated from the isolated total RNA using ReverTra Ace qPCR RT master mix with gDNA remover (Toyobo, Osaka, Japan). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The primers to measure gene expression levels were adapted from previous reports . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Gene expression was measured by real-time PCR using a Rotor-Gene Q PCR machine and SYBR green (Qiagen, Hilden, Germany). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | To estimate cell proliferation, the SRB assay was applied. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Two cell lines were exposed continuously to KCC-07 for 2 days prior to DNA damage induction by either etoposide (ETP) or phleomycin (Phleo). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | At the indicated time points, cells were fixed with 10% trichloroacetic acid (Sigma-Aldrich). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The 0 time point represents 1 hour after either ETP or Phleo treatments. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Fixed cells were stained with 0.4% SRB (in 1% acetic acid solution, Sigma-Aldrich) followed by dissolving in 10 mM Tris base (Millipore, MA, USA), and the color intensity was measured with a microplate spectrophotometer (BioTek plate reader, Agilent Technologies, CA, USA) at 540 nm. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Alternatively, cell viability was measured by MTT assay (AkrivisBio, CA, USA). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The cells were treated with KCC-07 and/or DNA damaging reagents as indicated in the figures. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The MTT procedure was followed as the manufacturer suggests, and the final metabolite was quantified at 590 nm. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Changes in cell cycle were analyzed after 72 hour exposure to KCC-07 and/or DNA damage reagent treatment for 24 hours. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Cells were fixed with ethanol and then treated with RNase A (100 μg/ml, Macherey-Nagel, Duren, Germany). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Propidium iodide (PI, Sigma-Aldrich) was used to stain cells followed by flow cytometry analysis (Fluorescence-Activated Cell Sorting, FACS) using FACSCanto II (BD Biosciences, NY, USA) with FACSDiva software (v9.2, BD Biosciences). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | For cell death analysis in vitro, two cell lines were seeded onto 12-well plates and exposed to the drug conditions described in the figure. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Cells were maintained at 37°C with 5% CO2 during live cell monitoring. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | PI stained cells, which are indicative of disintegrated cell membranes, were imaged and quantified by the IncuCyte live cell analysis system (Sartorius, Gottingen, Germany). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Cell lysates from KCC-07 and/or DNA damaging reagent treatments were obtained in a lysis buffer containing 60 mM Tris buffer pH 6.8, 2.4% sodium dodecyl sulfate (SDS), 6% β-mercaptoethanol, 0.12% bromophenol blue, and 12% glycerol. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Proteins were separated in SDS-PAGE gels and transferred onto nitrocellulose membranes (Cytiva, MA, USA). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Western blot bands were visualized by enhanced chemiluminescence (ECL, Bio-Rad Laboratories, CA, USA or Cytiva, MA, USA). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | When necessary, nuclear and cytoplasmic fractionation was applied. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Cells were lysed in 10 mM HEPES, pH 7.4, 10 mM KCl, 1.5 mM MgCl2, 0.34 M sucrose, 10% glycerol, 0.1% Triton X-100, 1 mM dithiothreitol (DTT). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | After centrifugation at 1,300 rcf, the soluble supernatants were further centrifuged at 13,000 rpm for the cytosolic fraction, and the insoluble pellet was lysed in 20 mM Tris, pH 8.0, 0.4 M NaCl, 15% glycerol, 1.5% Triton X-100, also containing MNase (micrococcal nuclease, Worthington Biochemical, NJ, USA) followed by centrifugation at 16,000 rcf. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The soluble fraction from this step constituted the nuclear fraction. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The antibodies used for Western blot analysis were ATM (Abcam, Cambridge, UK), ATM-pS1981 (Cell Signaling Technology, MA, USA), KAP1 (Novus Biologicals, CO, USA), KAP1-pS824 (Novus Biologicals), CHK2 (Millipore, MA, USA), CHK2-pT68 (Novus Biologicals), γ-H2AX (Cell Signaling Technology), p53 (Santa Cruz Biotechnology, TX, USA), p53-pS15 (Cell Signaling Technology), MDM2 (Santa Cruz Biotechnology), GAPDH (Genetex, CA, USA), and histone H3 (Abcam). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Quantified data were analyzed statistically using Prism Software (GraphPad, CA, USA). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | P values less than 0.05 were considered statistically significant (*<0.05, **<0.01, ***<0.001). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | First, we tested whether KCC-07 could affect cell growth of U-87MG and SH-SY5Y cell lines, which are neural origin tumors. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Although the two cell lines showed different sensitivity to KCC-07, both cell lines displayed dose dependent cell viability in response to KCC-07 using MTT assay (Fig. 1A). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | In addition, we examined the response of cell viability upon DNA damage induction. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Both cell lines were susceptible to Phleo or ETP, and these susceptibilities were not affected by KCC-07 treatment (Fig. 1B). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | These data suggest the possibility of expanding KCC-07 usage to other types of brain tumor cells. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | We also confirmed that the SH-SY5Y cell line is more susceptible to DNA damage than U-87MG . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Since KCC-07 could trigger p53 signaling , p53 status after treatment with KCC-07 and/or DNA damaging reagents was examined by Western blot. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | As a transcriptional activator and tumor suppressor, p53 must accumulate in the nucleus upon exposure to stress , which we observed in U-87MG and SH-SY5Y cell lines after KCC-07 treatment as well as DNA damage induction (Fig. 1C). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The location of MDM2, a specific E3 ubiquitin ligase for p53, was not changed after stress exposure. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | These data demonstrated that KCC-07’s therapeutic expansion to other brain tumor types, including glioblastoma and neuroblastoma, likely via p53 stabilization in both cell lines, which consequently reduced tumor cell proliferation rates. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Next, we examined what changes were induced in this experimental condition regarding p53 signaling. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | KCC-07 treatment induced CDKN1A (also known as p21, which is involved in cell cycle arrest in a p53 dependent manner) expression in both cell lines. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The increased CDKN1A expression was also detected after DNA damage induction, with a greater increment observed in SH-SY5Y cells, suggestive of higher sensitivity to DNA damage. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | However, no additive effect on CDKN1A expression was detected in combined treatment with KCC-07 and DNA damage induction (Fig. 2A). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | On the other hand, BBC3 (also known as PUMA, which is involved in cell death in a p53 dependent manner) expression was not increased by KCC-07 treatment, but was significantly increased following treatments with DNA damaging reagents. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Combined exposure to KCC-07 and DNA damaging reagents did not increase BBC3 expression further, except in U-87MG with combined treatment, which rather reduced its expression (Fig. 2B). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | These data indicate that the main consequence of KCC-07 treatment on U-87MG and SH-SY5Y cell lines is likely related to cell cycle progression rather than activation of cell death, similar to the previous report . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Furthermore, the immediate event upon DNA damage, which is called DDR, was investigated. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Upon DNA damage, particularly DNA DSBs which can be induced by either Phleo or ETP treatment, ATM is immediately auto-phosphorylated at serine (S) 1981, then phosphorylates several substrates including KAP1 at S824, CHK2 at threonine (T) 68, p53 at S15, and H2AX at S139 (called γH2AX) . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Western blot analyses indicate that proper phosphorylation modifications of ATM kinase substrates occurred after DNA damage induction, which was not affected by co-treatment with KCC-07 (Fig. 2C). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Of note, γH2AX signals were higher or maintained over time in cell line samples exposed to both KCC-07 and DNA damaging reagents. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | γH2AX signals are indicative of DNA strand breaks; therefore, these data suggest that the DNA repair process was likely compromised by combined treatment with KCC-07 (Fig. 2C), implying additive effects of the combined treatment. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The possible outcomes of DNA damage induction are either cell cycle arrest or cell death . |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | Therefore, we looked into both consequences. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | By applying FACS analysis, cell populations at each cell cycle phase were calculated. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | In general, DNA damage triggered G2/M arrest in both U-87MG and SH-SY5Y cell lines (Fig. 3A). |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | The DNA damaging conditions we applied to cell lines did not significantly increase cell populations arrested at G1 phase. |
PMC12426421 | KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells | However, combined treatments with KCC-07 and DNA damaging reagents shifted the cell populations toward the G1 phase except for U-87MG with Phleo treatment, whose cell line was relatively resistant to this type of DNA damaging reagent (Fig. 3A), similar to previous reports . |
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