Romani Arianna, Zauli Enrico, Zauli Giorgio, AlMesfer Saleh, Al-Swailem Samar, Voltan Rebecca
Department of Environmental and Prevention Sciences and Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA) Centre, University of Ferrara, Ferrara, Italy.
Department of Translational Medicine, University of Ferrara, Ferrara, Italy.
Front Oncol. 2022 Oct 20;12:1000677. doi: 10.3389/fonc.2022.1000677. eCollection 2022.
MDM2 is the principal inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The half-life of p53 is very short in normal cells and tissues, and an uncontrolled increase in p53 levels has potential harmful effects. It has been shown that p53 is frequently mutated in most cancers; however, p53 mutations are rare in retinoblastoma. Therefore, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. In this minireview, we discuss the potential use of nutlin-3, the prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for the treatment of retinoblastoma. Although p53 has pleiotropic biological effects, the functions of p53 depend on its sub-cellular localization. In the nucleus, p53 induces the transcription of a vast array of genes, while in mitochondria, p53 regulates mitochondrial metabolism. This review also discusses the relative contribution of p53-mediated gene transcription and mitochondrial perturbation for retinoblastoma treatment.
MDM2是p53的主要抑制剂，MDM2抑制剂可破坏MDM2与p53之间的物理相互作用。在正常细胞和组织中，p53的半衰期很短，p53水平不受控制地升高具有潜在有害影响。研究表明，p53在大多数癌症中经常发生突变；然而，p53突变在视网膜母细胞瘤中很少见。因此，旨在提高野生型p53表达水平的治疗策略具有吸引力。在本综述中，我们讨论了nutlin-3（一种破坏MDM2-p53相互作用的原型小分子抑制剂）在视网膜母细胞瘤治疗中的潜在用途。尽管p53具有多效性生物学效应，但其功能取决于其亚细胞定位。在细胞核中，p53诱导大量基因的转录，而在线粒体中，p53调节线粒体代谢。本综述还讨论了p53介导的基因转录和线粒体扰动对视网膜母细胞瘤治疗的相对贡献。
