Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine (Hematology/Oncology), The Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19103, USA.
Biochem Pharmacol. 2010 Sep 1;80(5):724-30. doi: 10.1016/j.bcp.2010.04.031. Epub 2010 May 5.
Tumor suppressor p53 is a transcription factor that guards the genome stability and normal cell growth. Stresses like DNA damage, oncogenic assault will turn on p53 function which leads to cell cycle arrest for DNA repair, senescence for permanent growth arrest or apoptosis for programmed cell death. At the late stage of cancer progression, p53 is hijacked in all forms of tumors either trapped in the negative regulator such as MDM2/viral proteins or directly mutated/deleted. Re-introduction of a functional p53 alone has been proven to induce tumor regression robustly. Also, an active p53 pathway is essential for effective chemo- or radio-therapy. The emerging cyclotherapy in which p53 acts as a chemoprotectant of normal tissues further expands the utility of p53 activators. Functionally, it is unquestionable that drugging p53 will render tumor-specific intervention. One direct method is to deliver the functional wild-type (wt) p53 to tumors via gene therapy. The small molecule strategies consist of activation of p53 family member such as p73, manipulating p53 posttranslational modulators to increase wt p53 protein levels, protein-protein interaction inhibitors to free wt p53 from MDM2 or viral protein, and restoring p53 function to mutant p53 by direct modulation of its conformation. Although most of the current pre-clinical leads are in microM range and need further optimization, the success in proving that small molecules can reactivate p53 marks the beginning of the clinical development of p53-based cancer therapy.
肿瘤抑制因子 p53 是一种转录因子，可保护基因组稳定性和正常细胞生长。 如 DNA 损伤、致癌攻击等压力会激活 p53 功能，导致细胞周期停滞以进行 DNA 修复、衰老以实现永久性生长停滞或细胞凋亡以实现程序性细胞死亡。 在癌症进展的后期阶段，p53 在所有形式的肿瘤中都被劫持，要么被困在负调节剂（如 MDM2/病毒蛋白）中，要么直接发生突变/缺失。 已证明单独重新引入功能正常的 p53 可强力诱导肿瘤消退。 此外，p53 通路的活性对于有效的化疗或放疗至关重要。 新兴的周期治疗学中，p53 作为正常组织的化学保护剂，进一步扩大了 p53 激活剂的应用。 从功能上讲，用药物治疗 p53 无疑将实现肿瘤特异性干预。 一种直接的方法是通过基因治疗将功能性野生型（wt）p53 递送至肿瘤。 小分子策略包括激活 p53 家族成员（如 p73）、操纵 p53 翻译后修饰调节剂以增加 wt p53 蛋白水平、蛋白-蛋白相互作用抑制剂以将 wt p53 从 MDM2 或病毒蛋白中释放出来，以及通过直接调节其构象来恢复突变 p53 的功能。 尽管目前大多数临床前先导化合物的浓度在微摩尔范围内，需要进一步优化，但成功证明小分子可以重新激活 p53 标志着基于 p53 的癌症治疗的临床开发的开始。
