Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil.
Medicinal & Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, São Paulo, Brazil.
Invest New Drugs. 2021 Aug;39(4):1139-1149. doi: 10.1007/s10637-021-01066-w. Epub 2021 Jan 21.
Despite the great advances in the understanding of the molecular basis of acute leukemia, very little of this knowledge has been translated into new therapies. Stathmin 1 (STMN1), a phosphoprotein that regulates microtubules dynamics, is highly expressed in acute leukemia cells and promotes cell cycle progression and proliferation. GDP366 has been described as a STMN1 and survivin inhibitor in solid tumors. This study identified structural GDP366 analogs and the cellular and molecular mechanisms underlying their suppressive effects on acute leukemia cellular models. STMN1 mRNA levels were higher in AML and ALL patients, independent of risk stratification (all p < 0.001). Cheminformatics analysis identified three structural GDP366 analogs, with AD80 more potent and effective than GSK2606414 and GW768505A. In acute leukemia cells, GDP366 and AD80 reduced cell viability and autonomous clonal growth in a dose- and/or time-dependent manner (p < 0.05) and induced apoptosis and cell cycle arrest (p < 0.05). At the molecular level, GDP366 and AD80 reduced Ki-67 (a proliferation marker) expression and S6 ribosomal protein (a PI3K/AKT/mTOR effector) phosphorylation, and induced PARP1 (an apoptosis marker) cleavage and γH2AX (a DNA damage marker) expression. GDP366 induced STMN1 phosphorylation and survivin expression, while AD80 reduced survivin and STMN1 expression. GDP366 and AD80 modulated 18 of the 84 cytoskeleton regulators-related genes. These results indicated that GDP366 and AD80 reduced the PI3K/STMN1 axis and had cytotoxic effects in acute leukemia cellular models. Our findings further highlight STMN1-mediated signaling as a putative anticancer target for acute leukemia.
尽管在急性白血病的分子基础理解方面取得了重大进展，但这些知识很少转化为新的治疗方法。Stathmin 1（STMN1）是一种调节微管动力学的磷酸化蛋白，在急性白血病细胞中高度表达，并促进细胞周期进程和增殖。GDP366 已被描述为实体瘤中的 STMN1 和 survivin 抑制剂。本研究鉴定了 GDP366 的结构类似物，并阐明了它们对急性白血病细胞模型抑制作用的细胞和分子机制。AML 和 ALL 患者的 STMN1 mRNA 水平升高，与风险分层无关（均 p<0.001）。化学信息学分析确定了三种 GDP366 的结构类似物，其中 AD80 比 GSK2606414 和 GW768505A 更有效。在急性白血病细胞中，GDP366 和 AD80 以剂量和/或时间依赖性方式降低细胞活力和自主克隆生长（p<0.05），并诱导细胞凋亡和细胞周期停滞（p<0.05）。在分子水平上，GDP366 和 AD80 降低了 Ki-67（增殖标志物）的表达和 S6 核糖体蛋白（PI3K/AKT/mTOR 效应物）的磷酸化，并诱导了 PARP1（凋亡标志物）的切割和 γH2AX（DNA 损伤标志物）的表达。GDP366 诱导 STMN1 磷酸化和 survivin 表达，而 AD80 降低 survivin 和 STMN1 的表达。GDP366 和 AD80 调节了 84 个细胞骨架调节剂相关基因中的 18 个。这些结果表明，GDP366 和 AD80 降低了 PI3K/STMN1 轴，并在急性白血病细胞模型中具有细胞毒性作用。我们的研究结果进一步强调了 STMN1 介导的信号转导作为急性白血病潜在的抗癌靶点。
