Glioblastoma multiforme (GBM), one of the most malignant brain cancers, responds poorly to chemotherapy and surgery. Transcription factor EB (TFEB) is markedly overexpressed in GBM cells. We investigated whether TFEB contributes to resistance to genotoxic stress and whether its inhibition promotes apoptosis of GBM cells and glioma stem cells (GSCs). Specifically, we examined whether combined treatment with etoposide and SAHA overcomes TFEB-mediated resistance and enhances apoptotic cell death. We examined the effects of etoposide, a topoisomerase II inhibitor, and SAHA, a histone deacetylase inhibitor, on TFEB expression and apoptotic signaling in human GBM cells and GSCs. To assess TFEB-mediated drug resistance, we measured cell viability, proliferation, and tumorsphere formation following single or combined treatments. Apoptotic signaling was analyzed by western blotting, MTT assays, and tumorsphere formation assays. Functional roles of TFEB were further investigated using overexpression and shRNA knockdown approaches. Treatment with etoposide induced apoptosis and reduced TFEB expression in GBM cells. Co-treatment with etoposide and SAHA synergistically increased cleaved PARP and phosphorylated H2AX levels, indicating enhanced apoptotic activity. In TFEB-overexpressing and knockdown GBM cells, apoptosis sensitivity varied according to TFEB expression levels. In GSCs, combination treatment significantly suppressed cell proliferation and tumorsphere formation, accompanied by reduced TFEB expression and oligomerization, and increased apoptosis. Our findings suggest that TFEB promotes the chemoresistance of GBM tumors and GSCs by suppressing apoptosis. Co-treatment with etoposide and SAHA inhibits TFEB activity and enhances apoptotic cell death, representing a promising therapeutic strategy for treating malignant brain tumors.

2025-11-02·EXPERT OPINION ON THERAPEUTIC PATENTS

Topoisomerase II inhibitors in oncology: an updated patent review (2016-present)

Review

作者: Maffei, Francesca ; Fimognari, Carmela ; Milelli, Andrea ; Turrini, Eleonora

INTRODUCTION:

Topoisomerase (topo) II inhibitors continue to represent a promising approach in anticancer therapy, although their clinical application is hampered by drug resistance and dose limiting toxicities.

AREA COVERED:

We performed a critical analysis of patent literature from January 2016 to January 2025 on topo II inhibitors in oncology using the online databases Espacenet, Wipo, and Google patent.

EXPERT OPINION:

Substantial progress in the development of novel topo II inhibitors through synthetic chemistry, natural product isolation, molecular modification, and in silico screening was recorded. These compounds belong to different chemical classes and mainly exhibit in vitro cytotoxicity in a low micromolar range, comparable to or greater than that induced by clinically established topo II inhibitors such as doxorubicin and etoposide. Some patented compounds showed catalytic inhibition of topo II enzyme, offering a safer and more effective alternative to topo II poisons. Despite encouraging in vitro data, only a few patents provide in vivo data or mechanistic insights, and none have progressed to clinical trials, highlighting a gap between preclinical innovation and clinical translation. Future research needs advancing in clinical development to fully realize the therapeutic potential of next-generation topo II inhibitors.

2025-09-22·Journal of biomolecular structure & dynamics

A quinoxaline-based derivative exhibited potent and selective anticancer activity with apoptosis induction in PC-3 cells through Topo II inhibition

Article

作者: Tawfik, Mohamed M. ; Barakat, Lamiaa A. A. ; Elsakka, Mayada E. G. ; Nafie, Mohamed S.

Quinoxaline constitutes a variety of derivatives that exhibit a range of biological characteristics, including anti-inflammatory and antitumor effects, and their importance in therapeutic chemistry is rising. The cytotoxicity effects of four quinoxaline compounds (I, II, III, and IV) against liver cancer cells (HepG2), prostate cancer cells (PC-3), and normal cells (Vero) were evaluated using the MTT assay. Compounds III and IV had the most anti-proliferative effects and highly selective indices against PC-3 cells with IC₅₀ values of 4.11 and 2.11 µM, respectively. The apoptotic cell death for compounds III and IV in PC-3 cells was investigated using cell cycle, Annexin V-FITC/PI double staining-based flow cytometry, and DNA fragmentation assay. Compounds III or IV arrested the cell cycle at the S phase and caused apoptosis in PC-3 cells. Compounds III and IV showed inhibitory effects against topoisomerase II enzyme with IC₅₀ values 21.98 and 7.529 µM, respectively, when compared to doxorubicin as a reference drug. Western Blot analysis displayed that compound IV treatment has significantly upregulated the pro-apoptotic proteins (p53, caspase-3, caspase-8) and downregulated the anti-apoptotic protein Bcl-2 in PC-3 cells in a dose-dependent manner, leading to cell apoptosis. The molecular docking study exhibited that compound IV had a good binding affinity for inhibiting topoisomerase II, consistent with the apoptotic mechanism. In vivo study using Ehrlich solid tumor model demonstrated that compound IV significantly reduced tumor volume and weight in vivo with minimal toxicity. This study reveals significant evidence for the antitumor efficacy of compound IV against prostate cancer cells as a topoisomerase II inhibitor.

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