Marín-Ramos Nagore I, Alonso Dulce, Ortega-Gutiérrez Silvia, Ortega-Nogales Francisco J, Balabasquer Moisés, Vázquez-Villa Henar, Andradas Clara, Blasco-Benito Sandra, Pérez-Gómez Eduardo, Canales Ángeles, Jiménez-Barbero Jesús, Marquina Ana, del Prado Jaime Moscoso, Sánchez Cristina, Martín-Fontecha Mar, López-Rodríguez María L
‡CEI Campus Moncloa, UCM-UPM and CSIC, E-28040 Madrid, Spain.
∥Instituto de Investigación Hospital 12 de Octubre, E-28041 Madrid, Spain.
J Med Chem. 2015 May 14;58(9):3757-66. doi: 10.1021/jm5019252. Epub 2015 May 4.
Angiogenesis is a requirement for the sustained growth and proliferation of solid tumors, and the development of new compounds that induce a sustained inhibition of the proangiogenic signaling generated by tumor hypoxia still remains as an important unmet need. In this work, we describe a new antiangiogenic compound (22) that inhibits proangiogenic signaling under hypoxic conditions in breast cancer cells. Compound 22 blocks the MAPK pathway, impairs cellular migration under hypoxic conditions, and regulates a set of genes related to angiogenesis. These responses are mediated by HIF-1α, since the effects of compound 22 mostly disappear when its expression is knocked-down. Furthermore, administration of compound 22 in a xenograft model of breast cancer produced tumor growth reductions ranging from 46 to 55% in 38% of the treated animals without causing any toxic side effects. Importantly, in the responding tumors, a significant reduction in the number of blood vessels was observed, further supporting the mechanism of action of the compound. These findings provide a rationale for the development of new antiangiogenic compounds that could eventually lead to new drugs suitable for the treatment of some types of tumors either alone or in combination with other agents.
血管生成是实体瘤持续生长和增殖的必要条件，开发能够持续抑制肿瘤缺氧产生的促血管生成信号的新化合物仍然是一个重要的未满足需求。在这项工作中，我们描述了一种新的抗血管生成化合物（22），它在缺氧条件下抑制乳腺癌细胞中的促血管生成信号。化合物22阻断MAPK途径，损害缺氧条件下的细胞迁移，并调节一组与血管生成相关的基因。这些反应由HIF-1α介导，因为当化合物22的表达被敲低时，其作用大多消失。此外，在乳腺癌异种移植模型中给予化合物22，在38%的治疗动物中使肿瘤生长减少46%至55%，且未引起任何毒副作用。重要的是，在有反应的肿瘤中，观察到血管数量显著减少，进一步支持了该化合物的作用机制。这些发现为开发新的抗血管生成化合物提供了理论依据，这些化合物最终可能导致适合单独或与其他药物联合治疗某些类型肿瘤的新药。
