一种天然提取的小分子化合物通过缓解 p53 依赖性的 CDK2/Rb 信号抑制和蜗牛驱动的 EMT,抑制小鼠的肿瘤生长和转移

IF 4 2区 医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE Chinese Journal of Natural Medicines Pub Date : 2024-02-01 DOI:10.1016/S1875-5364(24)60550-9
Boxue REN , Yang LI , Lei DI , Ranran CHENG , Lijuan LIU , Hongmei LI , Yi LI , Zhangrui TANG , Yongming YAN , Tao LU , Rong FU , Yongxian CHENG , Zhaoqiu WU
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引用次数: 0

摘要

肿瘤抑制蛋白 p53 是癌症生物学的核心,重新激活其通路已成为肿瘤学中一种前景广阔的治疗策略。这项研究介绍了一种新型化合物 LZ22,它能选择性地抑制表达野生型 p53 的肿瘤细胞的生长、迁移和转移,对不含 p53 或表达突变型 p53 的细胞无效。LZ22 的作用机制涉及与 MDM2 蛋白的组氨酸-96 口袋的高亲和性相互作用。这种相互作用破坏了 MDM2 与 p53 的结合,从而通过保护 p53 免受蛋白酶体降解而使其稳定。LZ22 通过恢复 p53 对 CDK2/Rb 信号通路的依赖性抑制,阻碍了细胞周期的进展并减少了细胞增殖。此外,LZ22 还能缓解 p53 依赖性抑制蜗牛转录因子的表达及其随之而来的 EMT,从而有效减少肿瘤细胞的迁移和远端转移。重要的是,肿瘤小鼠服用LZ22不会产生明显的副作用。这些发现使 LZ22 成为一种结构独特的 p53 再激活剂,为治疗野生型 TP53 人类癌症带来了希望。
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A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT

The tumor suppressor protein p53 is central to cancer biology, with its pathway reactivation emerging as a promising therapeutic strategy in oncology. This study introduced LZ22, a novel compound that selectively inhibits the growth, migration, and metastasis of tumor cells expressing wild-type p53, demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant p53. LZ22's mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 protein. This interaction disrupted the MDM2-p53 binding, consequently stabilizing p53 by shielding it from proteasomal degradation. LZ22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling pathway. Moreover, LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT, effectively reducing tumor cell migration and distal metastasis. Importantly, LZ22 administration in tumor-bearing mice did not manifest notable side effects. The findings position LZ22 as a structurally unique reactivator of p53, offering therapeutic promise for the management of human cancers with wild-type TP53.

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来源期刊
Chinese Journal of Natural Medicines
Chinese Journal of Natural Medicines INTEGRATIVE & COMPLEMENTARY MEDICINE-PHARMACOLOGY & PHARMACY
CiteScore
7.50
自引率
4.30%
发文量
2235
期刊介绍: The Chinese Journal of Natural Medicines (CJNM), founded and sponsored in May 2003 by China Pharmaceutical University and the Chinese Pharmaceutical Association, is devoted to communication among pharmaceutical and medical scientists interested in the advancement of Traditional Chinese Medicines (TCM). CJNM publishes articles relating to a broad spectrum of bioactive natural products, leading compounds and medicines derived from Traditional Chinese Medicines (TCM). Topics covered by the journal are: Resources of Traditional Chinese Medicines; Interaction and complexity of prescription; Natural Products Chemistry (including structure modification, semi-and total synthesis, bio-transformation); Pharmacology of natural products and prescription (including pharmacokinetics and toxicology); Pharmaceutics and Analytical Methods of natural products.
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