p53 通路作为癌症治疗靶点：障碍与前景。
The p53 pathway as a target in cancer therapeutics: obstacles and promise.
机构信息
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
出版信息
Sci Transl Med. 2011 Jan 5;3(64):64rv1. doi: 10.1126/scitranslmed.3001366.
Abstract
A large fraction of human tumors carry p53 mutations, which allow tumor initiation and progression; furthermore, it is now clear that restoration or reactivation of wild-type p53 function prompts rapid elimination of tumors. The discovery and design of compounds that reactivate or enhance the p53 pathway has resulted in the identification of promising drug candidates that have now entered clinical trials for anticancer strategies. However, some of these agents appear to elicit undesirable toxic effects on normal cells and tissues and therefore are restricted in the dose that can be applied in tumors. In this Review, we discuss the concerns about and promise of these p53 activators and propose ways to expand and optimize screening strategies to identify such molecules.
摘要
很大一部分人类肿瘤携带 p53 突变，这些突变允许肿瘤的起始和进展；此外，现在已经清楚的是，恢复或重新激活野生型 p53 功能会促使肿瘤迅速消除。重新激活或增强 p53 途径的化合物的发现和设计导致了有希望的候选药物的鉴定，这些药物现在已经进入了抗癌策略的临床试验。然而，这些药物中的一些似乎对正常细胞和组织产生了不良的毒性作用，因此在肿瘤中的应用剂量受到限制。在这篇综述中，我们讨论了对这些 p53 激活剂的关注和承诺，并提出了扩大和优化筛选策略以识别此类分子的方法。
相似文献
1
The p53 pathway as a target in cancer therapeutics: obstacles and promise.p53 通路作为癌症治疗靶点：障碍与前景。
Sci Transl Med. 2011 Jan 5;3(64):64rv1. doi: 10.1126/scitranslmed.3001366.
2
Small-molecule inhibitors of MDM2 as new anticancer therapeutics.MDM2 的小分子抑制剂作为新型抗癌治疗药物。
Semin Cancer Biol. 2010 Feb;20(1):10-8. doi: 10.1016/j.semcancer.2009.10.003. Epub 2009 Nov 6.
3
Small molecule compounds targeting the p53 pathway: are we finally making progress?靶向p53通路的小分子化合物：我们终于取得进展了吗？
Apoptosis. 2014 Jul;19(7):1055-68. doi: 10.1007/s10495-014-0990-3.
4
Targeting mutant p53 for efficient cancer therapy.针对突变型 p53 进行有效的癌症治疗。
Nat Rev Cancer. 2018 Feb;18(2):89-102. doi: 10.1038/nrc.2017.109. Epub 2017 Dec 15.
5
Pharmacological reactivation of p53 as a strategy to treat cancer.作为治疗癌症的策略，药理学激活 p53。
J Intern Med. 2015 Feb;277(2):248-259. doi: 10.1111/joim.12336.
6
P53: an ubiquitous target of anticancer drugs.P53：抗癌药物的一个普遍靶点。
Int J Cancer. 2002 Mar 10;98(2):161-6. doi: 10.1002/ijc.10158.
7
Reactivation of mutant p53 by capsaicin, the major constituent of peppers.辣椒的主要成分辣椒素使突变型p53重新激活。
J Exp Clin Cancer Res. 2016 Sep 6;35(1):136. doi: 10.1186/s13046-016-0417-9.
8
Drugging the p53 pathway: understanding the route to clinical efficacy.靶向 p53 通路：探索通往临床疗效的途径。
Nat Rev Drug Discov. 2014 Mar;13(3):217-36. doi: 10.1038/nrd4236.
9
Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents.鉴定新型 p53 通路激活小分子化合物揭示了与已知治疗药物的意想不到的相似性。
PLoS One. 2010 Sep 27;5(9):e12996. doi: 10.1371/journal.pone.0012996.
10
Pharmacological reactivation of mutant p53: from protein structure to the cancer patient.突变型 p53 的药理学再激活：从蛋白质结构到癌症患者。
Oncogene. 2010 Jul 29;29(30):4245-52. doi: 10.1038/onc.2010.188. Epub 2010 May 24.
引用本文的文献
1
Current perspectives in drug targeting intrinsically disordered proteins and biomolecular condensates.药物靶向内在无序蛋白质和生物分子凝聚物的当前观点。
BMC Biol. 2025 May 6;23(1):118. doi: 10.1186/s12915-025-02214-x.
2
Targeting p53-p21 signaling to enhance mesenchymal stem cell regenerative potential.靶向p53-p21信号通路以增强间充质干细胞的再生潜能。
Regen Ther. 2025 Apr 7;29:352-363. doi: 10.1016/j.reth.2025.03.007. eCollection 2025 Jun.
3
Synergistic impacts of rifampicin and doxorubicin against thioacetamide-induced hepatocellular carcinoma in rats.利福平与阿霉素对硫代乙酰胺诱导的大鼠肝细胞癌的协同作用
Liver Res. 2023 Nov 25;7(4):352-360. doi: 10.1016/j.livres.2023.11.005. eCollection 2023 Dec.
4
Side-stepping the guardian of the genome: current cancer therapeutics targeting mutant p53.避开基因组守护者：当前针对突变型p53的癌症治疗方法
Front Pharmacol. 2025 Jan 29;16:1529483. doi: 10.3389/fphar.2025.1529483. eCollection 2025.
5
Nanomedicine mediated thyroid cancer diagnosis and treatment: an approach from generalized to personalized medicine.纳米医学介导的甲状腺癌诊断与治疗：从通用医学到个性化医学的方法
Discov Oncol. 2024 Dec 18;15(1):789. doi: 10.1007/s12672-024-01677-8.
6
p53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications.肺癌中的p53基因学与生物学：见解、影响及临床应用
Biomedicines. 2024 Jun 29;12(7):1453. doi: 10.3390/biomedicines12071453.
7
Pre-clinical lung squamous cell carcinoma mouse models to identify novel biomarkers and therapeutic interventions.用于鉴定新型生物标志物和治疗干预措施的临床前肺鳞状细胞癌小鼠模型。
Front Oncol. 2023 Sep 25;13:1260411. doi: 10.3389/fonc.2023.1260411. eCollection 2023.
8
USP7 Inhibition Suppresses Neuroblastoma Growth via Induction of p53-Mediated Apoptosis and EZH2 and N-Myc Downregulation.USP7 抑制通过诱导 p53 介导的细胞凋亡和 EZH2、N-Myc 下调抑制神经母细胞瘤生长。
Int J Mol Sci. 2023 Sep 7;24(18):13780. doi: 10.3390/ijms241813780.
9
Hacking the Immune Response to Solid Tumors: Harnessing the Anti-Cancer Capacities of Oncolytic Bacteria.破解实体瘤的免疫反应：利用溶瘤细菌的抗癌能力
Pharmaceutics. 2023 Jul 21;15(7):2004. doi: 10.3390/pharmaceutics15072004.
10
Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage.p53 异构体比例的改变控制着乳腺癌细胞对 DNA 损伤的反应命运。
Cell Death Dis. 2022 Oct 28;13(10):907. doi: 10.1038/s41419-022-05349-9.
本文引用的文献
1
The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor.Mdm2 和 p53 的关系不断演变：Mdm2 作为癌基因和肿瘤抑制因子发挥双重作用。
Genes Dev. 2010 Aug 1;24(15):1580-9. doi: 10.1101/gad.1941710.
2
The p53 orchestra: Mdm2 and Mdmx set the tone.p53 乐团：MDM2 和 MDMX 定调。
Trends Cell Biol. 2010 May;20(5):299-309. doi: 10.1016/j.tcb.2010.01.009. Epub 2010 Feb 19.
3
SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53.SCH529074 是一种突变型 p53 的小分子激活剂，它可以结合 p53 DNA 结合域（DBD），恢复突变型 p53 的生长抑制功能，并中断 HDM2 介导的野生型 p53 的泛素化。
J Biol Chem. 2010 Apr 2;285(14):10198-212. doi: 10.1074/jbc.M109.083469. Epub 2010 Feb 2.
4
Identification and characterization of the first small molecule inhibitor of MDMX.鉴定和表征第一个 MDMX 的小分子抑制剂。
J Biol Chem. 2010 Apr 2;285(14):10786-96. doi: 10.1074/jbc.M109.056747. Epub 2010 Jan 15.
5
An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals.一种 MDM2 拮抗剂（MI-319）恢复了 p53 的功能，并延长了经口治疗的滤泡性淋巴瘤荷瘤动物的寿命。
Mol Cancer. 2009 Dec 3;8:115. doi: 10.1186/1476-4598-8-115.
6
Awakening guardian angels: drugging the p53 pathway.唤醒守护天使：抑制 p53 通路。
Nat Rev Cancer. 2009 Dec;9(12):862-73. doi: 10.1038/nrc2763.
7
The first 30 years of p53: growing ever more complex.p53的头30年：愈发复杂
Nat Rev Cancer. 2009 Oct;9(10):749-58. doi: 10.1038/nrc2723.
8
When mutants gain new powers: news from the mutant p53 field.当突变体获得新能力时：来自突变型p53领域的消息。
Nat Rev Cancer. 2009 Oct;9(10):701-13. doi: 10.1038/nrc2693. Epub 2009 Aug 20.
9
Modes of p53 regulation.p53的调控模式。
Cell. 2009 May 15;137(4):609-22. doi: 10.1016/j.cell.2009.04.050.
10
p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug.p53通过诱导MDM2介导的Slug降解来控制癌细胞的侵袭。
Nat Cell Biol. 2009 Jun;11(6):694-704. doi: 10.1038/ncb1875. Epub 2009 May 17.
Zotero 插件