T-cell malignancies are still difficult to treat due to a paucity of plans that target critical dependencies. Drug-induced cellular senescence provides a permanent cell cycle arrest during tumorigenesis and cancer development, particularly when combined with senolytics to promote apoptosis of senescent cells, which is an innovation for cancer therapy. Here, our research found that wogonin, a well-known natural flavonoid compound, not only had a potential to inhibit cell growth and proliferation but also induced cellular senescence in T-cell malignancies with nonlethal concentration. Transcription activity of senescence-suppression human telomerase reverse transcriptase (hTERT) and oncogenic C-MYC was suppressed in wogonin-induced senescent cells, resulting in the inhibition of telomerase activity. We also substantiated the occurrence of DNA damage during the wogonin-induced aging process. Results showed that wogonin increased the activity of senescence-associated β-galactosidase (SA-β-Gal) and activated the DNA damage response pathway mediated by p53. In addition, we found the upregulated expression of BCL-2 in senescent T-cell malignancies because of the antiapoptotic properties of senescent cells. Following up this result, we identified a BCL-2 inhibitor Navitoclax (ABT-263), which was highly effective in decreasing cell viability and inducing apoptotic cell death in wogonin-induced senescent cells. Thus, the “one-two punch” approach increased the sensibility of T-cell malignancies with low expression of BCL-2 to Navitoclax. In conclusion, our research revealed that wogonin possesses potential antitumor effects based on senescence induction, offering a better insight into the development of novel therapeutic methods for T-cell malignancies.

中文翻译：

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一二冲疗法治疗涉及 p53 依赖性细胞衰老的 T 细胞恶性肿瘤

由于缺乏针对关键依赖性的计划，T 细胞恶性肿瘤仍然难以治疗。药物诱导的细胞衰老在肿瘤发生和癌症发展过程中提供了永久性的细胞周期停滞，特别是当与 senolytics 结合以促进衰老细胞的凋亡时，这是癌症治疗的一项创新。在这里，我们的研究发现汉黄芩素是一种著名的天然类黄酮化合物，不仅具有抑制细胞生长和增殖的潜力，而且在非致死浓度的 T 细胞恶性肿瘤中诱导细胞衰老。抑制衰老的人端粒酶逆转录酶 ( hTERT ) 和致癌C-MYC的转录活性在汉黄芩素诱导的衰老细胞中被抑制，导致端粒酶活性受到抑制。我们还证实了汉黄芩诱导的衰老过程中 DNA 损伤的发生。结果表明汉黄芩素增加了衰老相关的β-半乳糖苷酶（SA - β-Gal) 并激活 p53 介导的 DNA 损伤反应途径。此外，由于衰老细胞的抗凋亡特性，我们发现 BCL-2 在衰老 T 细胞恶性肿瘤中的表达上调。根据这一结果，我们鉴定了一种 BCL-2 抑制剂 Navitoclax (ABT-263)，它在降低汉黄芩素诱导的衰老细胞中的细胞活力和诱导凋亡细胞死亡方面非常有效。因此，“一两拳”方法增加了 BCL-2 低表达的 T 细胞恶性肿瘤对 Navitoclax 的敏感性。总之，我们的研究表明，汉黄芩素具有基于衰老诱导的潜在抗肿瘤作用，为开发治疗 T 细胞恶性肿瘤的新方法提供了更好的见解。