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Article Open Access

C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC

  • Authors:
    • Eunsun Jung
    • Yoon-Jae Kim
    • Kyoungmin Lee
    • Seojin Jang
    • Soeun Park
    • Eunhye Oh
    • Minsu Park
    • Seongjae Kim
    • Dongmi Ko
    • Yong Koo Kang
    • Kee Dal Nam
    • Lee Farrand
    • Cong-Truong Nguyen
    • Minh Thanh La
    • Jihyae Ann
    • Jeewoo Lee
    • Ji Young Kim
    • Jae Hong Seo

  • View Affiliations / Copyright

    Affiliations: Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152‑703, Republic of Korea, Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152‑703, Republic of Kore, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia, Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
    Copyright: © Jung et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 13
    |
    Published online on: November 11, 2025
       https://doi.org/10.3892/or.2025.9018
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Abstract

Treatment options for triple‑negative breast cancer (TNBC) are limited because they typically harbor a high cancer stem‑like population and exhibit a relatively aggressive metastatic phenotype. Heat shock protein 90 (HSP90), a molecular chaperone that regulates diverse oncogenic client proteins, has emerged as a compelling therapeutic target owing to its involvement in key tumor‑promoting processes, such as uncontrolled proliferation, angiogenesis and metastasis. Owing to the undesirable induction of a compensatory heat shock response (HSR) and systemic toxicity, classical N‑terminal inhibitors of HSP90 have failed in clinical trials. The impact of a rationally designed novel inhibitor of the HSP90 C‑terminus in TNBC cells was investigated. NCT‑58 eliminates rapidly proliferating tumor cells accompanied by simultaneous degradation of AKT, MEK and STAT3, and effectively eradicates the cancer stem‑like population (breast cancer stem cells) in both human MDA‑MB‑231 and murine 4T1 cells. The latter phenomenon is accompanied by reductions in the activity of ALDH1 and the CD44high/CD24low stem‑like population, as well as impairment of mammosphere formation. Furthermore, NCT‑58 markedly impairs cell migration, coinciding with the collapse of HSP90 client cytoskeletal proteins, including vimentin and F‑actin, in MDA‑MB‑231 cells in vitro. A synergistic effect was observed when NCT‑58 was combined with paclitaxel or doxorubicin in MDA‑MB‑231 cells. Collectively, these findings indicated that targeting the C‑terminal domain of HSP90 with NCT‑58 is a promising therapeutic strategy for the treatment of molecularly heterogeneous TNBC.
View Figures

Figure 1

NCT-58 exerts anti-proliferative effect in TNBC cells by targeting the C-terminal domain of HSP90. (A) Four TNBC cell lines, MDA-MB-231, BT549, Hs578T and 4T1 cells were treated with various concentrations of NCT-58 (0–20 µM) for 72 h. Cell viability was assessed using MTS assay, and IC50 values were calculated using non-linear regression with a sigmoidal dose-response curve. (B) MDA-MB-231 and 4T1 cells were treated at the indicated concentrations of NCT-58 (0–10 µM) for 72 h. Apoptosis was determined through sub-G1-DNA analysis using flow cytometry. (C) Immunoblot analyses of PARP, cleaved-PARP, caspase-3, cleaved caspase-3, caspase-7 and cleaved caspase-7 protein expression in MDA-MB-231 cells after treatment with NCT-58 (0–10 µM, 72 h). GAPDH was used as an internal loading control. Quantitative graphs of these protein levels. The results are presented as the mean ± SEM of at least three independent experiments and analyzed using one-way ANOVA followed by Bonferroni's post hoc test. (D) Effect of NCT-58 on C-terminal HSP90 binding activity. The inhibitory effect of HSP90 inhibitors (NCT-58, novobiocin or geldanamycin, 500 µM) on the interaction between HSP90α (C-terminal) and its co-chaperone peptidylprolyl isomerase was determined using an HSP90α (C-terminal) inhibitor screening assay. (E) Influence of NCT-58 on N-terminal HSP90 binding activity. The competitive HSP90α binding activity of HSP90 inhibitors (NCT-58, novobiocin or geldanamycin, 1 µM) with FITC-labeled geldanamycin was determined using an HSP90α N-terminal domain assay. (F and G) Molecular docking analysis of NCT-58 binding to the CTD of HSP90 (PDB ID: 7RY1). (F) The binding pose of NCT-58 at the dimerization interface is displayed as a space-filling model. The α1 chain of HSP90 is rendered in a blue ribbon, and the α2 chain in a pink ribbon. Connolly surface representation of the HSP90 CTD, with NCT-58 modeled within the binding interface (docking score=−9.5). (G) A 2D interaction diagram of NCT-58 with key residues in the HSP90 CTD. Hydrogen bonds and π-anion interactions are indicated by dashed green and blue lines, respectively. (H and I) Comparison of the effects of NCT-58 and the N-terminal HSP90 inhibitor geldanamycin on HSF-1 and HSP70 expression. MDA-MB-231 cells were treated with NCT-58 (300 nM and 10 µM) or geldanamycin (300 nM) for 24 h. Cells were immuno-stained for HSF-1 (red, H) or HSP70 (green, I) using DAPI (nuclei, blue). Images were acquired using a confocal microscope, and quantification of immunofluorescence intensity was performed using ImageJ software. Nuclear HSF1 intensity was expressed as the HSF1/DAPI ratio, and cytoplasmic HSP70 intensity was expressed as corrected total cell fluorescence normalized to DAPI. (J and K) Effect of NCT-58 and geldanamycin on cytotoxicity in non-malignant cells. Normal human mammary epithelial MCF10A (J) and 293 (K) cells were treated with various concentrations (0.1–10 µM) of NCT-58 or geldanamycin for 72 h. Cell viability was determined using MTS assay (***P<0.001). *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001. TNBC, triple-negative breast cancer; Gelda, geldanamycin; Novo, novobiocin; CTD, C-terminal domain.

Figure 2

NCT-58 downregulates expression of pro-survival client proteins in triple-negative breast cancer cells. (A) MDA-MB-231 and 4T1 cells were cultured in the presence or absence of NCT-58 (0–10 µM) for 72 h. Expression levels of HSP90 client proteins such as AKT, phospho-AKT (Ser473), MEK and phospho-MEK (Ser218/222) were detected through immunoblotting. GAPDH was used as a loading control. (B) Quantitative graphs represent the ratio of expression of these proteins relative to GAPDH expression after treatment with NCT-58. (C) Immunoblot analyses of STAT3, phospho-STAT3 (Tyr705), protein levels of cyclin D1 and survivin in MDA-MB-231 and 4T1 cells after treatment with NCT-58 (0–10 µM, 72 h). (D) Quantitative graphs of these proteins levels. The results are presented as the mean ± SEM of at least three independent experiments and analyzed using one-way ANOVA followed by Bonferroni's post hoc test. *P<0.05, **P<0.01 and ***P<0.001.

Figure 3

NCT-58 suppresses cancer stem-like properties and migratory activity in TNBC cells. (A and B) Effect of NCT-58 (0–10 µM, 72 h) on ALDH1 activity in (A) MDA-MB-231 and (B) 4T1 cells. The specific inhibitor diethyl-amino-benzaldehyde was used to define the Aldefluor-positive population. Aldefluor-positive cells were quantified using flow cytometry (right panel). (C) Effect of NCT-58 (0–10 µM, 72 h) on the CD44high/CD24low stem-like population in MDA-MB-231 cells. The CD44high/CD24low population was quantified through flow cytometry. (D) Effect of NCT-58 on mammosphere formation in vitro. 4T1 cells (5×104 cells/ml) were cultured in ultralow attachment plates in the presence or absence of NCT-58 (2–5 µM, 5 days). The number and volume of mammospheres were quantified using optical microscopy. (E and F) After exposure to NCT-58 (10 µM) for 48 h, MDA-MB-231 cells were immuno-stained for vimentin (1:100, E) and F-actin (1:100, Texas Red-X phalloidin, F) with DAPI nuclear stain (blue). (G and H) Effect of NCT-58 on TNBC cell migration. (G) After exposure to NCT-58 (0–20 µM) in MDA-MB-231 and 4T1 cells, kinetic analysis of cell migration was determined using the IncuCyte™ Live-Cell Imaging System and quantified for the indicated time duration. The kinetic graphs of cell migration represent the relative wound density. (H) Relative wound density (%) in MDA-MB-231 cells at 50 h and in 4T1 cells at 25 h, respectively. The results are presented as the mean ± SEM of at least three independent experiments and analyzed using one- or two-way ANOVA followed by Bonferroni's post hoc test. *P<0.05, **P<0.01 and ***P<0.001. TNBC, triple-negative breast cancer.

Figure 4

Synergistic effects of combining NCT-58 with paclitaxel or doxorubicin in triple-negative breast cancer cells. (A-F) MDA-MB-231 cells were treated with the indicated concentrations of NCT-58 (0–15 µM) and paclitaxel (0–2 µM, A-C) or doxorubicin (0–3 µM, D-F) for 72 h and cell viability was assessed using MTS assay. The isobologram plot, heat map (% inh., Inhibition rate), and CI were analyzed to assess the drug-drug synergy of various dose combinations of NCT-58 with paclitaxel or doxorubicin. Isobologram plot and average CI values were generated using the CompuSyn software to quantify drug interactions, where CI<1 indicates synergism, CI=1 indicates an additive effect, and CI>1 indicates antagonism. (i, antagonism; ii, addictive effect; iii, moderate synergism; iv, synergism; and v, strong synergism). The heat map depicts relative cell viability compared with the DMSO control. CI, combination index.
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Copy and paste a formatted citation
Spandidos Publications style
Jung E, Kim Y, Lee K, Jang S, Park S, Oh E, Park M, Kim S, Ko D, Kang YK, Kang YK, et al: C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC. Oncol Rep 55: 13, 2026.
APA
Jung, E., Kim, Y., Lee, K., Jang, S., Park, S., Oh, E. ... Seo, J.H. (2026). C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC. Oncology Reports, 55, 13. https://doi.org/10.3892/or.2025.9018
MLA
Jung, E., Kim, Y., Lee, K., Jang, S., Park, S., Oh, E., Park, M., Kim, S., Ko, D., Kang, Y. K., Nam, K. D., Farrand, L., Nguyen, C., La, M. T., Ann, J., Lee, J., Kim, J. Y., Seo, J. H."C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC". Oncology Reports 55.1 (2026): 13.
Chicago
Jung, E., Kim, Y., Lee, K., Jang, S., Park, S., Oh, E., Park, M., Kim, S., Ko, D., Kang, Y. K., Nam, K. D., Farrand, L., Nguyen, C., La, M. T., Ann, J., Lee, J., Kim, J. Y., Seo, J. H."C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC". Oncology Reports 55, no. 1 (2026): 13. https://doi.org/10.3892/or.2025.9018
Copy and paste a formatted citation
x
Spandidos Publications style
Jung E, Kim Y, Lee K, Jang S, Park S, Oh E, Park M, Kim S, Ko D, Kang YK, Kang YK, et al: C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC. Oncol Rep 55: 13, 2026.
APA
Jung, E., Kim, Y., Lee, K., Jang, S., Park, S., Oh, E. ... Seo, J.H. (2026). C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC. Oncology Reports, 55, 13. https://doi.org/10.3892/or.2025.9018
MLA
Jung, E., Kim, Y., Lee, K., Jang, S., Park, S., Oh, E., Park, M., Kim, S., Ko, D., Kang, Y. K., Nam, K. D., Farrand, L., Nguyen, C., La, M. T., Ann, J., Lee, J., Kim, J. Y., Seo, J. H."C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC". Oncology Reports 55.1 (2026): 13.
Chicago
Jung, E., Kim, Y., Lee, K., Jang, S., Park, S., Oh, E., Park, M., Kim, S., Ko, D., Kang, Y. K., Nam, K. D., Farrand, L., Nguyen, C., La, M. T., Ann, J., Lee, J., Kim, J. Y., Seo, J. H."C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC". Oncology Reports 55, no. 1 (2026): 13. https://doi.org/10.3892/or.2025.9018
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