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. 2025 Aug 31;34(4):138–146. doi: 10.5607/en25017

KCC-07, MBD2 Inhibitor, Expands the Therapeutic Window of DNA Damage Inducing Reagents in Neural Tumor Cells

Darom Lee 1,2,†, Junyoung Kim 1,2,†, Keeeun Kim 1, Youngsoo Lee 1,2,3,*
PMCID: PMC12426421  PMID: 40925882

Abstract

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. 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. Here we demonstrate KCC-07 treatment’s application to other neural tumors. KCC-07 treatment reduced proliferation rates of U-87MG (glioma cell line) and SH-SY5Y (neuroblastoma cell line). p53 stabilization occurred in these cell lines without significantly affecting programmed cell death factors under KCC-07 exposure. Furthermore, tumor cell growth inhibition was enhanced when combined with DNA damaging reagents. 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. 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.

Keywords: Neural tumor, DNA damage, KCC-07, MBD2 inhibitor, p53

INTRODUCTION

The hallmarks of cancer have been updated a couple of times since first proposed by Hanahan and Weinberg in 2000 [1]. 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) [2]. The expanded cancer hallmarks now contain 4 more entities: ‘unlocking phenotype plasticity’, ‘senescent cells’, ‘polymorphic microbiomes’, and ‘nonmutational epigenetic reprogramming’ [3]. DNA modification, particularly methylation, is one form of nonmutational epigenetic event, and CpG methylation causes gene silencing [4, 5]. Several enzymes and proteins are involved in DNA methylation, including DNA methyltransferases (DNMTs), 5’-methylcytosine hydroxylases (TETs), and methyl-CpG binding domain (MBD) proteins [4]. The MBD protein family consists of eleven proteins including MBD1 to MBD6, which function as DNA methylation readers in gene repression [6, 7]. Alterations of MBD proteins, particularly MBD1 to MBD4, have been found in several tumors including prostate, endometrial, and brain tumors [6].

In particular, MBD2 has functional impacts on hematopoietic and solid tumors. Reduction or inhibition of MBD2 is advantageous in tumor treatment [7]. 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. 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 [8]. 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-{[(3S)-2,3-dihydro-1,4-benzodioxin-3-yl]methyl}-acetamide) were suggested as novel candidates, yet the biological effects of these potential MBD2 inhibitors were not verified [9, 10], which places KCC-07 in a unique position for this purpose.

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 [11, 12]. 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. Chemotherapeutic agents inducing DNA damage activate p53 signaling, leading to cell cycle arrest and programmed cell death to prevent tumor progression [11-14].

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. Here we tested whether the effect of DNA damaging reagents on neural tumor cells can be augmented with KCC-07 exposure. 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.

MATERIALS AND METHODS

Cell lines and reagents

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). 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. KCC-07 (3-[4-(2-Pyridinyl)-2-thiazolyl]amino]phenol (CAS 315702-75-1)) was obtained from Selleckchem (TX, USA). Phleomycin (Phleo, CAS 11006-33-0) and etoposide (ETP, CAS 33419-42-0) were purchased from Sigma (MO, USA). When necessary, reagents were dissolved in DMSO (dimethyl sulfoxide). Each experimental condition of drug treatments is indicated in the figures.

RNA extraction and real-time PCR

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). The primers to measure gene expression levels were adapted from previous reports [15, 16]. Gene expression was measured by real-time PCR using a Rotor-Gene Q PCR machine and SYBR green (Qiagen, Hilden, Germany).

Sulforhodamine B (SRB) and dimethylthiazol diphenyltetrazolium bromide (MTT) assay

To estimate cell proliferation, the SRB assay was applied. Two cell lines were exposed continuously to KCC-07 for 2 days prior to DNA damage induction by either etoposide (ETP) or phleomycin (Phleo). At the indicated time points, cells were fixed with 10% trichloroacetic acid (Sigma-Aldrich). The 0 time point represents 1 hour after either ETP or Phleo treatments. 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. Alternatively, cell viability was measured by MTT assay (AkrivisBio, CA, USA). The cells were treated with KCC-07 and/or DNA damaging reagents as indicated in the figures. The MTT procedure was followed as the manufacturer suggests, and the final metabolite was quantified at 590 nm.

Cell cycle analysis and live cell imaging for cell death detection

Changes in cell cycle were analyzed after 72 hour exposure to KCC-07 and/or DNA damage reagent treatment for 24 hours. Cells were fixed with ethanol and then treated with RNase A (100 μg/ml, Macherey-Nagel, Duren, Germany). 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). 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. Cells were maintained at 37°C with 5% CO2 during live cell monitoring. PI stained cells, which are indicative of disintegrated cell membranes, were imaged and quantified by the IncuCyte live cell analysis system (Sartorius, Gottingen, Germany).

Western blot analysis

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. Proteins were separated in SDS-PAGE gels and transferred onto nitrocellulose membranes (Cytiva, MA, USA). Western blot bands were visualized by enhanced chemiluminescence (ECL, Bio-Rad Laboratories, CA, USA or Cytiva, MA, USA). When necessary, nuclear and cytoplasmic fractionation was applied. 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). 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. The soluble fraction from this step constituted the nuclear fraction. 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).

Statistical analysis

Quantified data were analyzed statistically using Prism Software (GraphPad, CA, USA). P values less than 0.05 were considered statistically significant (*<0.05, **<0.01, ***<0.001).

RESULTS AND DISCUSSION

U-87MG and SH-SY5Y cell lines are sensitive to KCC-07

First, we tested whether KCC-07 could affect cell growth of U-87MG and SH-SY5Y cell lines, which are neural origin tumors. 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). In addition, we examined the response of cell viability upon DNA damage induction. Both cell lines were susceptible to Phleo or ETP, and these susceptibilities were not affected by KCC-07 treatment (Fig. 1B). These data suggest the possibility of expanding KCC-07 usage to other types of brain tumor cells. We also confirmed that the SH-SY5Y cell line is more susceptible to DNA damage than U-87MG [17]. Since KCC-07 could trigger p53 signaling [8], p53 status after treatment with KCC-07 and/or DNA damaging reagents was examined by Western blot. As a transcriptional activator and tumor suppressor, p53 must accumulate in the nucleus upon exposure to stress [18], which we observed in U-87MG and SH-SY5Y cell lines after KCC-07 treatment as well as DNA damage induction (Fig. 1C). The location of MDM2, a specific E3 ubiquitin ligase for p53, was not changed after stress exposure. 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.

Fig. 1.

Fig. 1

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KCC-07 suppresses growth of U-87MG and SH-SY5Y cell lines. (A) Dose dependent proliferation responses of U-87MG and SH-SY5Y cell lines to KCC-07 as measured by MTT assay. Both U-87MG (glioma cell line) and SH-SY5Y (neuroblastoma cell line) are sensitive to KCC-07 treatment in a dose dependent manner. Representative data are shown in the graphs (n=12). The readouts of the NT group were set as 100%, then the survival rates were calculated as a relative values to the NT group. Each experiment was repeated twice independently. (B) Dose dependent proliferation responses of U-87MG and SH-SY5Y cell lines to DNA damage induced by either phleomycin (Phleo) or etoposide (ETP) in combination with KCC-07 exposure as measured by MTT assay. Dose dependency of DNA damage inducing drugs is not affected by KCC-07 treatment. Representative data are shown in the graphs (n=4~6). The readouts of the NT group were set as 100%, then the survival rates were calculated as a relative values to the NT group. Each experiment was repeated twice independently. (C) Detection of p53 stabilization in the nucleus following KCC-07 treatment and DNA damage induction, indicating the activation of p53 signaling in both U-87MG and SH-SY5Y cell lines. The distribution of MDM2, an E3 ubiquitin ligase for p53, was not changed; its localization is restricted to the cytosol. Representative data are shown in the figure. Each experiment was repeated three times independently. The experimental conditions of drug treatments are indicated in the figure. NT, Not treated; NS, not significant; C, cytosolic fraction; N, nuclear fraction.

KCC-07 treatment induces p53 dependent signaling

Next, we examined what changes were induced in this experimental condition regarding p53 signaling. 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. 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. However, no additive effect on CDKN1A expression was detected in combined treatment with KCC-07 and DNA damage induction (Fig. 2A). 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. 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). 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 [8].

Fig. 2.

Fig. 2

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Both KCC-07 and DNA damage induction result in known p53 dependent gene expression. (A) Induction of CDKN1A expression, which is p53 dependent and involved in cell cycle regulation, by either KCC-07 or DNA damaging reagent treatments measured by real-time PCR. Combined treatment with KCC-07 and DNA damaging reagents did not further increase CDKN1A expression in both cell lines. The SH-SY5Y cell line is more sensitive to DNA damaging reagents. The gene expression levels were normalized by β-actin real-time PCR readout. Representative data are shown in the graphs (n=3). Each experiment was repeated twice independently. (B) Induction of BBC3 expression, which is p53 dependent and involved in apoptosis, by DNA damaging reagents. KCC-07 treatment did not induce BBC3 expression in both cell lines. The gene expression levels were normalized by β-actin real-time PCR readout. Representative data are shown in the graphs (n=3). Each experiment was repeated twice independently. (C) Consistent DNA damage response (DDR) following combined treatment with KCC-07 and DNA damaging reagents analyzed by Western blots. Both cell lines displayed well-established DDR including ATM phosphorylation, KAP1 and CHK2 phosphorylation (ATM-dependent), and p53 activation (ATM-dependent) followed by induction of apoptotic and cell cycle arrest factors (p53-dependent, see B and C in this figure) upon DNA damage induction by Phleo or ETP treatments. KCC-07 addition does not change the proper DDR upon DNA damage, but sustained H2AX phosphorylation indicates defective DNA damage repair. Ponceau S staining and GAPDH western blot served as loading controls. Representative data are shown. Each experiment was repeated twice independently. The experimental conditions of drug treatments are indicated in the figure. NS, not significant.

Furthermore, the immediate event upon DNA damage, which is called DDR, was investigated. 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) [13, 14]. 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). Of note, γH2AX signals were higher or maintained over time in cell line samples exposed to both KCC-07 and DNA damaging reagents. 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.

Combined treatment with KCC-07 and DNA damage induction results in additive effects on tumor cell growth suppression

The possible outcomes of DNA damage induction are either cell cycle arrest or cell death [11, 12]. Therefore, we looked into both consequences. By applying FACS analysis, cell populations at each cell cycle phase were calculated. In general, DNA damage triggered G2/M arrest in both U-87MG and SH-SY5Y cell lines (Fig. 3A). The DNA damaging conditions we applied to cell lines did not significantly increase cell populations arrested at G1 phase. 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 [17, 19]. Next, we applied two different analyses to measure cell death. We further analyzed the FACS data, particularly cell populations at sub-G1 phase, in which cells undergo cell death. This cell population contained both floating cells in culture media and cells attached to the culture plate. We found additive effects on cell death indices in combined treatment groups with KCC-07 and DNA damaging reagents in both cell lines (Fig. 3B). Additionally, dead cells were measured in real-time by live cell imaging using IncuCyte. However, the dead cell index was not significantly different between cell lines with DNA damage induction and combined treatment (Fig. 3C), most likely due to measurement of only the attached cell population on the plate using IncuCyte. Of note, SH-SY5Y cell lines showed aggregation of cells upon KCC-07 treatment, which was also detected in combined treatment groups, indicating that cell response to KCC-07 might vary depending on cell lines. Moreover, we measured proliferation indices in continuous exposure to KCC-07 and/or DNA damaging reagents. There was further proliferation reduction in U-87MG and SH-SY5Y cell lines with combined treatment of KCC-07 and DNA damaging reagents compared to individual treatments (Fig. 4A), suggesting that additive effects on growth suppression of tumor cells could be achieved by combined treatment with KCC-07 and DNA damage induction.

Fig. 3.

Fig. 3

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Combined treatment with KCC-07 and DNA damaging reagents further induces cell death. (A) Changes in cell cycle phases following KCC-07 and/or DNA damaging reagent treatment. The left bar graphs represent percentages of each cell cycle phase, and the right graphs represent cell cycle profiles analyzed by FACS. G2/M arrest is the main response to DNA damaging reagent treatments, and combined treatments with KCC-07 and DNA damaging reagents shift the cell cycle profile toward G1 arrest except for the U-87MG cell line with phleomycin (Phleo) treatment, to which it is less sensitive. Representative data are shown in the graphs (n=3). Each experiment was repeated twice independently. (B) Changes in sub-G1 phase following KCC-07 and/or DNA damaging reagent treatment (from Fig. 3A above). Cell populations in the sub-G1 phase, which indicate cell death, include both floating cells in the culture media and cells attached to culture plates. Combined treatments with KCC-07 and DNA damaging reagents show additive effects on neural tumor cell death in general. Representative data are shown in the graphs (n=3). Each experiment was repeated twice independently. (C) Real-time cell death analysis by IncuCyte. The left line graphs indicate red-stained cell population during exposure to KCC-07 and/or DNA damaging reagents in real-time tracking. Only cells attached to culture plates were measured, due to the technical limitation of this analysis. The right panels show typical cell shape and red staining at the final time points. SH-SY5Y cells aggregate when they are exposed to KCC-07, which U-87MG cells do not. This might reflect higher sensitivity to KCC-07 treatment (see Fig. 1A). Representative data are shown in the graphs (n=3, each sample imaged at nine different spots in real-time). Each experiment was repeated twice independently. The experimental conditions of drug treatments are indicated in the figure. NS, not significant compared to controls.

Fig. 4.

Fig. 4

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Combined treatment with KCC-07 and DNA damaging reagents shows additive effects on suppression of tumor cell growth. Proliferation analysis following KCC-07 and/or DNA damaging reagent treatment measured by SRB assay. All combined treatments with KCC-07 and DNA damaging reagents show additive reduction of proliferation in U-87MG and SH-SY5Y cell lines. These data suggest the benefit of combined treatments with KCC-07, an epigenetic modifier via MBD2 inhibition, and DNA damaging reagents to treat brain tumors, which can minimize the side effects of DNA damaging reagent regimens. Representative data are shown in the graphs (n=6). Each experiment was repeated twice independently. The experimental conditions of drug treatments are indicated in the figure.

Collectively, these data demonstrate the expandable application of KCC-07 to other neural tumors and its potential to enhance the efficacy of existing treatments. The combination approach with KCC-07 suggested here could enable dose reduction of DNA damaging agents, substantially mitigating their associated toxicity while preserving or even enhancing therapeutic efficacy for brain tumors. In addition, further studies are warranted to identify the specific mediators that bridge MBD2 inhibition and p53 pathway activation in U-87MG and SH-SY5Y cell lines, which could provide valuable insights for optimizing KCC-07 based therapeutic strategies in neural tumors.

ACKNOWLEDGEMENTS

We thank the Three-Dimensional Immune System Imaging Core Facility at Ajou University School of Medicine. YSL was supported by NRF grants funded by the Korea government (MSIP) (RS-2017-NR021553 and RS-2022-NR069263). The authors declare no competing financial interests.

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