Ginkgo Biflavones Cause p53 Wild-Type Dependent Cell Death in a Transcription-Independent Manner of p53
Ginkgo Biflavones Cause p53 Wild-Type Dependent Cell Death in a Transcription-Independent Manner of p53
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银杏双黄酮以 p53 转录独立的方式导致 p53 野生型依赖性细胞死亡
DOI：
10.1021/acs.jnatprod.2c00959
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发表时间：
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影响因子：
5.1
通讯作者：
Ximing Xu
中科院分区：
文献类型：
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作者：
Siyu Zhang;Yujie Sun;Fengli Yao;Hongju Li;Yacong Yang;Xionghao Li;Zhongyue Bai;Yu Hu;Peng Wang;Ximing Xu
银杏作为一种传统和西方医学的药用植物，成为一种潜在的治疗药物，用于管理各种疾病，但银杏双黄酮（bilobetin，isoginkgetin和ginkgetin）在癌症治疗中的应用和潜在的作用机制仍然是难以捉摸的。在本研究中，我们确定银杏双黄酮作为潜在的p53激活剂，可以通过抑制MDM 2蛋白表达来提高p53蛋白表达水平。同时，它们诱导细胞死亡，而不依赖于p53转录活性。此外，银杏黄酮是银杏黄酮中的一个突出，通过诱导凋亡和G2/M期阻滞降低HCT-116细胞的存活。此外，银杏双黄酮还能显著诱导ROS的产生，从而导致铁凋亡。最后，我们提供的证据表明，银杏黄酮加强氟尿嘧啶（5-FU）在HCT-116结肠癌异种移植模型的抗肿瘤作用。综上所述，银杏双黄酮代表了一类新的p53激活剂，其依赖于p53野生型状态，并且作为潜在的抗癌剂值得进一步探索。
Ginkgo biloba, as a medicinal plant in both traditional and western medicine, emerged as a potential therapeutic agent for the management of a variety of diseases, but ginkgo biflavones (bilobetin, isoginkgetin, and ginkgetin) application in cancer therapy and underlying mechanisms of action remained elusive. In the present study, we identified ginkgo biflavones as potential p53 activators that could enhance p53 protein expression level by inhibiting MDM2 protein expression. At the same time, they induced cell death independent of p53 transcriptional activity. Moreover, ginkgetin was a standout among ginkgo biflavones that reduced the survival of HCT-116 cells by induction of apoptosis and G2/M phase arrest. Furthermore, ginkgo biflavones induced ROS generation significantly, which resulted in ferroptosis. Finally, we provide evidence that ginkgetin strengthened the antitumor effect of fluorouracil (5-FU) in the HCT-116 colon cancer xenograft model. To sum up, ginkgo biflavones represent a new class of p53 activator that depends on the p53 wild-type status and warrants further exploration as potential anticancer agents.