Department of Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China.
Mol Cancer Ther. 2022 Oct 7;21(10):1524-1534. doi: 10.1158/1535-7163.MCT-22-0119.
Reactivation of p53 tumor-suppressor function by small molecules is an attractive strategy to defeat cancer. A potent p53-reactivating molecule RITA, which triggers p53-dependent apoptosis in human tumor cells in vitro and in vivo, exhibits p53-independent cytotoxicity due to modifications by detoxification enzyme Sulfotransferase 1A1 (SULT1A1), producing a reactive carbocation. Several synthetic modifications to RITA's heterocyclic scaffold lead to higher energy barriers for carbocation formation. In this study, we addressed the question whether RITA analogs NSC777196 and NSC782846 can induce p53-dependent apoptosis without SULT1A1-dependent DNA damage. We found that RITA analog NSC782846, but not NSC777196, induced p53-regulated genes, targeted oncogene addiction, and killed cancer cells upon p53 reactivation, but without induction of DNA damage and inhibition RNA pol II. Our results might demonstrate a method for designing more specific and potent RITA analogs to accelerate translation of p53-targeting compounds from laboratory bench to clinic.
小分子激活抑癌基因 p53 的功能是战胜癌症的一种有吸引力的策略。一种有效的 p53 激活分子 RITA，在体外和体内可触发人类肿瘤细胞中 p53 依赖性凋亡，由于解毒酶 Sulfotransferase 1A1 (SULT1A1)的修饰而产生 p53 非依赖性细胞毒性，从而产生反应性碳正离子。对 RITA 的杂环骨架进行的几种合成修饰导致碳正离子形成的能垒更高。在这项研究中，我们提出了这样一个问题，即 RITA 类似物 NSC777196 和 NSC782846 是否可以在不依赖 SULT1A1 的 DNA 损伤的情况下诱导 p53 依赖性凋亡。我们发现，RITA 类似物 NSC782846 可诱导 p53 调节基因的表达、靶向致癌基因的依赖性以及在 p53 重新激活时杀死癌细胞，但不会诱导 DNA 损伤和抑制 RNA pol II。我们的研究结果可能为设计更特异和有效的 RITA 类似物提供了一种方法，以加速针对 p53 的化合物从实验室研究向临床应用的转化。
