Advanced extra-nodal natural killer/T-cell lymphoma (ENKTL) patients tend to be resistant to multiple chemotherapy drugs. Studies have shown that high expression of B-cell lymphoma 2 (BCL-2) is associated with poor prognosis and drug resistance of ENKTL, hence it is a potential therapy target. The BCL-2 homology (BH) domain 4 is essential for the anti-apoptotic function of BCL-2. Compared with BH3 domain, BH4 domain participates in more biological processes than just anti-apoptosis. Therefore, we tested the anti-tumor effect of BDA-366, a promising BCL-2 BH4 domain inhibitor, in treating ENKTL cells. The results showed that ENKTL cells were more sensitive to BDA-366 than other small-molecule inhibitors, such as ABT-199, S63845 and Chidamide. BDA-366 strongly induced apoptosis of ENKTL cells in vitro and significantly inhibited tumor growth in vivo with no obvious cytotoxicity to normal hematopoietic cells. Moreover, treatment with BDA-366 elevated reactive oxygen species (ROS) level and induced mitochondria damage in ENKTL cells, as evidenced by decreased mitochondrial membrane potential (MMP) and increased Ca²⁺ release. Gene Ontology (GO) enrichment analysis showed significant change of nuclear factor-kappaB (NF-κB) pathway in ENKTL cells treated with BDA-366, and by western blot, the expression of NF-κB p65 and mitochondrial function-related protein peroxisome proliferator-activated receptor γ coactivator-1β (PGC1β) were shown to be downregulated. In conclusion, as a BCL-2 BH4 domain antagonist, BDA-366 exhibited potent anti-tumor effect on ENKTL cells both in vitro and in vivo by triggering mitochondria-mediated apoptosis through suppressing NF-κB signaling pathway. Therefore, BDA-366 is a promising drug to treat ENKTL and overcome chemotherapy resistance.

2023-05-26·BMC cancer

CYD0281, a Bcl-2 BH4 domain antagonist, inhibits tumor angiogenesis and breast cancer tumor growth.

Article

作者: Ding, Yi ; Zhao, Yiling ; Li, Jiangchao ; Chen, Minggui ; Ding, Chunyong ; Zhang, Rongxin ; Chen, Jian ; Lin, Yihua ; Zhang, Qian-Qian ; Ding, Ye ; Zheng, Lingyun ; Li, Zishuo ; Qi, Cuiling ; Zhou, Jia ; Wang, Lijing ; Liu, Qiao

BACKGROUND:

B-cell lymphoma 2 (Bcl-2) family proteins are key regulators of apoptosis, which possess four conserved Bcl-2 homologies (BH) domains. Among the BH domains, the BH3 domain is considered as a potent 'death domain' while the BH4 domain is required for anti-apoptotic activity. Bcl-2 can be converted to a pro-apoptotic molecule through the removal or mutation of the BH4 domain. Bcl-2 is considered as an inducer of angiogenesis, which can promote tumor vascular network formation and further afford nutrients and oxygen to promote tumor progression. However, whether disrupting the function of the BH4 domain to convert Bcl-2 into a pro-apoptotic molecule could make Bcl-2 possess the potential for anti-angiogenic therapy remains to be defined.

METHODS:

CYD0281 was designed and synthesized according to the lead structure of BDA-366, and its function on inducing a conformational change of Bcl-2 was further evaluated via immunoprecipitation (IP) and immunofluorescence (IF) assays. Moreover, the function of CYD0281 on apoptosis of endothelial cells was analyzed via cell viability, flow cytometry, and western blotting assays. Additionally, the role of CYD0281 on angiogenesis in vitro was determined via endothelial cell migration and tube formation assays and rat aortic ring assay. Chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, breast cancer cell xenograft tumor on CAM and in mouse models as well as the Matrigel plug angiogenesis assay were used to explore the effects of CYD0281 on angiogenesis in vivo.

RESULTS:

We identified a novel potent small-molecule Bcl-2-BH4 domain antagonist, CYD0281, which exhibited significant anti-angiogenic effects both in vitro and in vivo, and further inhibited breast cancer tumor growth. CYD0281 was found to induce conformational changes in Bcl-2 through the exposure of the BH3 domain and convert Bcl-2 from an anti-apoptotic molecule into a cell death inducer, thereby resulting in the apoptosis of vascular endothelial cells.

CONCLUSIONS:

This study has revealed CYD0281 as a novel Bcl-2-BH4 antagonist that induces conformational changes of Bcl-2 to convert to a pro-apoptotic molecule. Our findings indicate that CYD0281 plays a crucial role in anti-angiogenesis and may be further developed as a potential anti-tumor drug candidate for breast cancer. This work also provides a potential anti-angiogenic strategy for breast cancer treatment.

2023-03-01·Science China-Materials

A donor-acceptor covalent organic framework as the promising construct for photothermal therapy

作者: Tang, Bo ; Hu, Hui ; Zhang, Huiwen ; Zhang, Jie ; Li, Na ; Zuo, Kaiming ; Gao, Yanan ; Pan, Wei ; Wan, Xiuyan

A donor-acceptor covalent organic framework (COF), TB-COF, constructed from an electron-rich building unit (donor) and an electron-deficient building unit (acceptor), was developed as a promising photothermal agent for photothermal therapy (PTT).Upon laser irradiation, significant photoinduced electron transfer (PET) occurs between the donor and acceptor in TB-COF, converting the absorbed optical energy to thermal energy and resulting in the ablation of tumor.TB-COF possessed satisfying photothermal conversion efficiency, reaching 43.65%, similar to materials commonly used for PTT.Moreover, hyaluronic acid (HA) was coated on TB-COF to improve its biocompatibility and achieve tumor targeting.Furthermore, in vitro and in vivo experiments confirmed satisfying photothermal anticancer efficacy of TB-COF-HA. [graphic not available: see fulltext]

100 项与 BDA-366 相关的药物交易

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