Laboratory of Education and Research in In Vitro Toxicology - Tox In, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, 74605-220, Brazil.
Laboratório de Química Farmacêutica Medicinal (LQFM), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, 74605-220, Brazil.
Fundam Clin Pharmacol. 2020 Aug;34(4):444-457. doi: 10.1111/fcp.12540. Epub 2020 Mar 14.
Our group designed and synthesized the N-phenyl-piperazine LQFM030 [1-(4-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl) piperazin-1-yl) ethanone], a small molecule derived from molecular simplification of the Nutlin-1, an inhibitor of the human homologue of murine double minute 2 (MDM2) protein that is expressed in several types of cancer. To better investigate the effects of LQFM030 regarding the p53 mutation status, this study investigated the antiproliferative activity of LQFM030 against the p53-null K562 leukemia cells as well as the cell death pathways involved. In addition, the effects of LQFM030 on the levels of the p53/MDM2 complex were also carried out using 3T3 cells as a p53 wild-type model. Our data suggest that LQFM030 triggered apoptosis in K562 cells via different mechanisms including cell cycle arrest, caspase activation, reduction of mitochondrial activity, decrease in MDM2 expression, and transcriptional modulation of MDMX, p73, MYC, and NF-ĸB. Additionally, it promoted effects in p53/MDM2 binding in p53 wild-type 3T3 cells. Therefore, LQFM030 has antiproliferative effects in cancer cells by a p53 mutation status-independent manner with different signaling pathways. These findings open new perspectives to the treatment of leukemic cells considering the resistance development associated with cancer treatment with conventional cytotoxic drugs.
我们小组设计并合成了 N- 苯基哌嗪 LQFM030[1-(4-((1-(4- 氯苯基)-1H-吡唑-4-基)甲基)哌嗪-1-基)乙酮]，这是一种小分子，来源于 Nutlin-1 的分子简化，Nutlin-1 是一种人源同源物二聚体 2（MDM2）蛋白的抑制剂，在几种类型的癌症中表达。为了更好地研究 LQFM030 对 p53 突变状态的影响，本研究调查了 LQFM030 对 p53 缺失的 K562 白血病细胞的抗增殖活性以及涉及的细胞死亡途径。此外，还使用 3T3 细胞作为 p53 野生型模型，研究了 LQFM030 对 p53/MDM2 复合物水平的影响。我们的数据表明，LQFM030 通过不同的机制触发 K562 细胞凋亡，包括细胞周期停滞、半胱天冬酶激活、线粒体活性降低、MDM2 表达减少以及 MDMX、p73、MYC 和 NF-ĸB 的转录调节。此外，它还促进了 p53 野生型 3T3 细胞中 p53/MDM2 结合的作用。因此，LQFM030 通过不同的信号通路，以 p53 突变状态独立的方式对癌细胞具有抗增殖作用。这些发现为治疗白血病细胞开辟了新的视角，考虑到与传统细胞毒性药物治疗相关的癌症耐药性的发展。
