bims-midomi 2025-03-30 papers

Cell Cycle. 2025 Mar 27. 1-18

Non-canonical functions of BCL-2 family members in energy metabolism and necrotic cell death regulation.

Mohamed El-Mesery, Franziska Rudolf, Yannick Heimann, Georg Häcker, Thomas Brunner.

The large family of BCL-2 proteins plays a well-established role in the regulation of mitochondrial apoptosis pathway, and the crosstalk between death receptor signaling and mitochondrial apoptosis. Accumulating evidence suggests, however, that various BCL-2 family members are also involved in the regulation of apoptosis-unrelated necrotic forms of cell death, and even non-cell death processes. In this review, we discuss the emerging role of BCL-2 family members, and in particular BIM, in the regulation of mitochondrial dynamics, morphology and energy metabolism, and associated consequences for drug-inuced necrotic cell death.

Keywords: BCL-2; apoptosis; electron transport chain; glycolysis; mitochondria; mitotoxicants

DOI: https://doi.org/10.1080/15384101.2025.2484868

Pharmaceuticals (Basel). 2025 Mar 11. pii: 393. [Epub ahead of print]18(3):

Sulforaphane from Brassica Oleracea Induces Apoptosis in Oral Squamous Carcinoma Cells via p53 Activation and Mitochondrial Membrane Potential Dysfunction.

Pooja Narain Adtani, Sura Ali Ahmed Fuoad Al-Bayati, Walid Shaaban Elsayed.

Background/Objectives: Oral squamous cell carcinoma (OSCC) is a significant global health concern, necessitating the development of novel treatment strategies. The present study investigated the in vitro anticancer activity of sulforaphane (SFN), an isothiocyanate derived from Brassica oleracea, on the OECM-1 human oral squamous carcinoma cell line. Methods: OECM-1 cells were cultured and exposed to a range of SFN concentrations. To assess the cell viability and determine the half maximal inhibitory concentration (IC50) of SFN following 24 h of treatment, an MTT assay was performed. Apoptosis was evaluated using AO/PI staining, a TUNEL assay, Annexin V-FITC analysis, and a DNA fragmentation assay. Changes in the mitochondrial membrane potential were analyzed using a JC-1 staining assay. A Western blot assay was performed to assess the expression levels of apoptosis-associated proteins (Bax, Bcl2, caspase-3, caspase-9, PARP, Smad-4, p53, cytochrome c, and GAPDH). Cell cycle analysis was performed to validate the apoptotic findings. Results: The IC50 concentration of SFN was 5.7 µM. The apoptotic assays demonstrated an effective induction of apoptosis in the OECM-1 cells. Western blot analysis demonstrated the dose-dependent upregulation of p53, caspase-3, caspase-9, PARP, cytochrome c, and Bax and the downregulation of the anti-apoptotic proteins Bcl-2 and Smad-4 after SFN treatment. Conclusions: The data obtained indicate that SFN has significant potential to induce apoptosis in OECM-1 cells by disrupting mitochondrial function and modulating apoptotic pathways. The outcomes of our research indicate SFN's potential as a viable treatment drug for OSCC.

Keywords: apoptosis; oral squamous cell carcinoma; sulforaphane

DOI: https://doi.org/10.3390/ph18030393

Cell Death Discov. 2025 Mar 26. 11(1): 120

BH3 mimetics augment cytotoxic T cell killing of acute myeloid leukemia via mitochondrial apoptotic mechanism.

Kapil Saxena, Shao-Hsi Hung, Esther Ryu, Shailbala Singh, Qi Zhang Tatarata, Zhihong Zeng, Zhe Wang, Marina Y Konopleva, Cassian Yee.

Adoptive cell therapy (ACT) can address an unmet clinical need for patients with relapsed/refractory acute myeloid leukemia (AML), but its effect is often modest in the setting of high tumor burden. In this study, we postulated that strategies to lower the AML apoptotic threshold will augment T cell killing of AML cells. BH3 mimetics, such as venetoclax, are a clinically approved class of compounds that predispose cells to intrinsic apoptosis by inhibiting anti-apoptotic mitochondrial proteins. We explored the anti-leukemic efficacy of BH3 mimetics combined with WT1-specific CD8+ T cells on AML cell lines and primary samples from patients with a diverse array of disease characteristics to evaluate if lowering the cellular apoptotic threshold via inhibition of anti-apoptotic mitochondrial proteins can increase leukemic cell sensitivity to T cell therapy. We found that the combination approach of BH3 mimetic and CD8+ T cells led to significantly increased killing of established AML lines as well as of adverse-risk primary AML leukemic blast cells. In contrast to the hypothesis that enhanced killing would be due to combined activation of the intrinsic and extrinsic apoptotic pathways, our data suggests that CTL-mediated killing of AML cells was accomplished primarily through activation of the intrinsic/mitochondrial apoptotic pathway. This highly effective combinatorial activity due to convergence on the mitochondrial apoptotic pathway was conserved across multiple AML cell lines and primary samples, suggesting that mitochondrial priming may represent a novel mechanism of optimizing adoptive cell therapy for AML patients.

DOI: https://doi.org/10.1038/s41420-025-02375-2