LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n.° 228, 4050-313, Porto, Portugal.
CIIMAR, Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n.° 228, 4050-313, Porto, Portugal.
Cancer Lett. 2019 Apr 1;446:90-102. doi: 10.1016/j.canlet.2019.01.014. Epub 2019 Jan 19.
TAp73 is a key tumor suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumors with impaired p53 signaling, like neuroblastoma, TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumor growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumor activity. Notably, LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53, enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumor cells. Importantly, LEM2 displayed potent antitumor activity against patient-derived neuroblastoma cells, consistent with an activation of the TAp73 pathway. Additionally, potent synergistic effects were obtained for the combination of LEM2 with doxorubicin and cisplatin in patient-derived neuroblastoma cells. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against neuroblastoma.
TAp73 是一种关键的肿瘤抑制蛋白，可调节独特和共享的 p53 靶基因的转录，这些基因在肿瘤发生和治疗反应中具有关键作用。因此，在 p53 信号受损的肿瘤中，如神经母细胞瘤，TAp73 的激活代表了一种令人鼓舞的策略，可替代 p53 的激活，以抑制肿瘤生长和化疗耐药性。在这项工作中，我们报告了一种新的 TAp73 激活剂，1-醛基-3,4-二甲氧基黄烷酮（LEM2），具有很强的抗肿瘤活性。值得注意的是，LEM2 能够将 TAp73 从与 MDM2 和突变型 p53 的相互作用中释放出来，从而增强 p53 缺失和突变型 p53 表达的肿瘤细胞中的 TAp73 转录活性、细胞周期停滞和细胞凋亡。重要的是，LEM2 对患者来源的神经母细胞瘤细胞表现出很强的抗肿瘤活性，与 TAp73 途径的激活一致。此外，在患者来源的神经母细胞瘤细胞中，LEM2 与多柔比星和顺铂联合使用时，显示出很强的协同作用。总之，除了对 TAp73 药理学的发展有重要贡献外，LEM2 可能为改善神经母细胞瘤的治疗选择铺平道路。
