Triple-negative breast cancer (TNBC) presents a significant challenge for treatment due to its aggressive nature and the lack of effective therapies. This study developed dual inhibitors against cell division cycle 25 (CDC25) and histone deacetylases (HDACs) for TNBC treatment. CDC25 phosphatases are crucial for activating cyclin-dependent kinases (CDKs), the master regulators of cell cycle progression. HDACs regulate various biological processes by deacetylating histone and non-histone proteins, affecting gene expression, chromatin structure, cell differentiation, and proliferation. Dysregulations of HDAC and CDC25 are associated with several human malignancies. We generated a group of dual inhibitors for CDC25 and HDAC by combining the molecular structures of CDC25 (quinoline-5,8-dione) and HDAC (hydroxamic acid or benzamide) pharmacophores. The newly developed compounds were evaluated against various solid-tumor, leukemia, and non-malignant breast epithelial cells. Among the synthesized compounds, 18A emerged as a potent inhibitor, demonstrating significant cytotoxicity against TNBC cells, superior to its effects on other cancer types while sparing non-malignant cells. 18A possessed similar HDAC inhibitory activity as MS-275 and potently suppressed CDC25 activity in vitro and the CDK1 dephosphorylation in cells. Additionally, 18A hindered the progression of S and G₂/M phases, triggered DNA damage, and induced apoptosis. These findings underscore the potential of 18A as a targeted therapy for TNBC and warrants further preclinical development.

2024-12-01·Toxicology in Vitro

Alteration in folate carrier expression via histone deacetylase inhibition in BeWo human placental choriocarcinoma cells

Article

作者: Miyazawa, Yuki ; Furugen, Ayako ; Kosugi, Haruna ; Narumi, Katsuya ; Kobayashi, Masaki ; Nishimura, Ayako ; Aoyagi, Ryoichi ; Umazume, Takeshi

Folates are essential nutrients for fetal development during pregnancy. Valproic acid (VPA), an inhibitor of histone deacetylases (HDACs), alters the expression of folate carriers in placental cells; however, the underlying mechanisms remain unclear. Here, we aimed to determine the profiles of folate carriers (folate receptor alpha [FOLR1], solute carrier [SLC]-19A1, and SLC46A1) after inhibition of HDACs, especially class I and IIa HDACs, using different inhibitors and gene knockdown tests. Quantitative polymerase chain reaction revealed that BeWo cells (a trophoblast model) expressed HDACs and folate carriers, similar to human placental villi. FOLR1 expression was upregulated by VPA, apicidin, and trichostatin A, but downregulated by MS-275 after 24 h treatment. VPA and apicidin upregulated the expression of SLC46A1. These inhibitors downregulated SLC19A1 expression. TMP269 (a class IIa inhibitor) did not affect folate carrier levels. HDAC1/2 knockdown upregulated FOLR1 and SLC46A1 levels, whereas HDAC1/3 knockdown downregulated FOLR1 levels. Our findings suggest that the pharmacological inhibition of class I HDACs alters the expression of folate carriers in BeWo cells. By contrast, HDAC inhibitors exert different regulatory effects on folate carriers. Moreover, HDAC1/2 inhibition may be a potential mechanism involved in altering FOLR1 and SLC46A1 levels.

2024-11-01·Journal of Cellular Physiology

RETRACTION: Impact of Histone Deacetylase Inhibitors SAHA and MS‐275 on DNA Repair Pathways in Human Mesenchymal Stem Cells

RETRACTION: G. Di Bernardo, N. Alessio, C. Dell'Aversana, F. Casale, D. Teti, M. Cipollaro, L. Altucci, and U. Galderisi, “Impact of Histone Deacetylase Inhibitors SAHA and MS‐275 on DNA Repair Pathways in Human Mesenchymal Stem Cells,” Journal of Cellular Physiology 225, no. 2 (2010): 537‐544, https://doi.org/10.1002/jcp.22236.The above article, published online on 17 March 2024 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor‐in‐Chief, Robert Heath; and Wiley Periodicals LLC. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed unambiguous image manipulation in Figure 3, SAHA ‐ H2O2 Treatment and SAHA – Untreated panels. The authors admitted to these image alterations, cooperated with the investigation, and were able to provide partial raw data of the article including some of the original, unmodified images. Nonetheless, the modification of the images to change the appearance is clearly against the ethical policy of the journal and Wiley's Best Practice Guidelines on Research Integrity and Publishing Ethics. In addition, based on the received partial raw data, regarding the positive cell counts for the 8oxodG assay, the journal team could not exclude that the visual modification of these images affects the number of counted 8oxodG‐positive cells, and consequently the related conclusions of the article. Therefore, the editors have lost confidence in the data presented and have decided to retract the article. The authors were informed of the decision to retract but did not agree to the retraction.

100 项与 MS-275 derivative 相关的药物交易

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