CANCER CELL
·
2020
·
IF 26.602
Shuo Chen,Jia-Le Wu,Ying Liang,Yi-Gang Tang,Hua-Xin Song,Li-Li Wu,Yang-Fei Xing,Ni Yan,Yun-Tong Li,Zheng-Yuan Wang,Shu-Jun Xiao,Xin Lu,Sai-Juan Chen,Min Lu
Summary TP53 is the most frequently mutated gene in cancer, yet these mutations remain therapeutically non-actionable. Major challenges in drugging p53 mutations include heterogeneous mechanisms of inactivation and the absence of broadly applicable allosteric sites. Here we report the identification of small molecules, including arsenic trioxide (ATO), an established agent in treating acute promyelocytic leukemia, as cysteine-reactive compounds that rescue structural p53 mutations. Crystal structures of arsenic-bound p53 mutants reveal a cryptic allosteric site involving three arsenic-coordinating cysteines within the DNA-binding domain, distal to the zinc-binding site. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif alongside the overall β-sandwich fold, endowing p53 mutants with thermostability and transcriptional activity. In cellular and mouse xenograft models, ATO reactivates mutant p53 for tumor suppression. Investigation of the 25 most frequent p53 mutations informs patient stratification for clinical exploration. Our results provide a mechanistic basis for repurposing ATO to target p53 mutations for widely applicable yet personalized cancer therapies.
研究领域:
肿瘤学
·
分子生物学
·
药理学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2020
·Vol. 10
·期 3
·2001029
·
IF 7.367
Shuo Huang,Linlin Zhang,Miaomiao Xu,Chao Li,Hongliang Fu,Jie Huang,Xin Jin,Sheng Liang,Hui Wang
New radionuclide-labeled targeting nanocarrier systems have generated new opportunities for tumor treatment and imaging. Nevertheless, such therapeutic strategy is clinically unfeasible on anaplastic thyroid carcinoma (ATC) patients, because of lacking suitable targets and resistance to radiation. In order to figure out a potential treatment, immuno-histochemical staining is performed in human ATC tissue species and high expression of cluster determinant 44 (CD44) is found. Therefore, a CD44-targeted delivery system is designed and constructed by self-assembly of tyrosine (Tyr)–hyaluronic acid (HA)–polyethyleneimine (PEI), which can radiolabel 131/125 I and load a p53 mutant restoring regent, Prima-1. The 125 I-labeled nanocomposites display an impressive tumor imaging as well as a long radiation treatment cycle. The 131 I-labeled nanoparticles show remarkable anti ATC-tumor effects in vitro and in vivo, due to radiosensitization of Prima-1 by reactivation of the p53 mutants.
研究领域:
纳米技术
·
肿瘤学
·
放射学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2016
·Vol. 5
·期 1
·77-88
·
IF 3.614
Chun Li,Junqing Hu,Wenyao Li,Guosheng Song,Jia Shen
Our previous work reported the development of a proteasome inhibitor, bortezomib (BTZ) encapsulated hollow mesoporous silica nanospheres (HMSNs), as a biocompatible and effective drug-delivery system for non-small cell lung cancer (NSCLC) therapy. Then we found that the tumor-suppressing effect of BTZ or HMSNs-BTZ was compromised in p53 null/mutant NSCLC. In fact, clinical studies have shown a beneficial effect of the combination of p53 gene therapy and chemotherapeutic drugs for patients with NSCLC, especially with the p53 gene null/mutant NSCLC. But there are some safety and toxicity concerns that face the use of gene delivery viral vectors. Here, HMSN-based co-delivery of BTZ and the tumor-suppressor gene p53 was developed for p53 signal impaired NSCLC therapy. The result of the cell viability assay on p53-mutant H1299 cells showed that the half-maximum inhibiting concentration (IC50) of HMSN-PEI-BTZ-p53 was 51% or 25% of that for HMSN-BTZ in 72 or 96 h treatment, respectively. Live/dead staining assay for treated H1299 cells exhibited wider distribution, and higher dead staining was prominent in the HMSNs-PEI-BTZ-p53 group when compared to that of the HMSNs-BTZ group with equivalent BTZ concentration, which was consistent with accumulated p53 expression. Furthermore, the Annexin V-FITC/PI assay suggested restored p53 expression by HMSNs-PEI-BTZ-p53 induced activation of early apoptosis which contributed to enhanced later cell death. Western blotting and real time PCR results showed that several p53 downstream genes responded strongly and synergistically to BTZ function and p53 restored expression (accumulation of p21 and bax, activation of caspase 3, down-regulation of Bcl-2, etc.). Restoration and re-activation of the p53 signal pathway was the basic molecular mechanism for enhanced efficacy of HMSNs-PEI-BTZ-p53 on p53-mutant NSCLC cells.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Bulletin
·
2024
·
IF 18.8
Shijie Li,Sarun Juengpanich,Win Topatana,Tianao Xie,Lidan Hou,Yiyuan Zhu,Jiadong Chen,Yukai Shan,Yina Han,Ziyi Lu,Tianen Chen,Charlie Topatana,Bin Zhang,Jiasheng Cao,Jiahao Hu,Jiafei Yan,Yingxin Chen,Zhen Gu,Jicheng Yu,Xiujun Cai,Mingyu Chen
Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal–organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment. Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species (ROS), which leads to a further increase in DNA damage, resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality. The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）