The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
Guangxi Medical University, Nanning 530021, China.
Biomed Pharmacother. 2017 Jul;91:1065-1074. doi: 10.1016/j.biopha.2017.05.025. Epub 2017 May 15.
The complexity of cancer has led to single-target agents exhibiting lower-than-desired clinical efficacy. Drugs with multiple targets provide a feasible option for the treatment of complex tumors. Multitarget anti-angiogenesis agents are among the new generation of anticancer drugs and have shown favorable clinical efficacy. Dianhydrogalactitol (DAG) is a chemotherapeutic agent for chronic myeloid leukemia and lung cancer. Recently, it has been tested in phase II trials of glioblastoma treatment; however, mechanisms of DAG in glioblastoma have not been elucidated. Here we show that DAG could inhibit the migration and invasion of U251 cell line by inhibiting matrix metalloproteinase-2 (MMP2) expression. Furthermore, DAG could also inhibit tumor angiogenesis in vitro as well as in the zebrafish model. Mechanistic studies reveal that DAG inhibited both VEGFR2 and FGFR1 pathways. Our results suggest that DAG may be a potential multitarget agent that can inhibit tumor migration, invasion, and angiogenesis, and the anti-angiogenic effects may be involved in dual-suppression VEGF/VEGFR2 and FGF2/FGFR1 signal pathways.
癌症的复杂性导致单靶标药物的临床疗效低于预期。具有多个靶标的药物为治疗复杂肿瘤提供了可行的选择。多靶点抗血管生成药物是新一代抗癌药物之一，具有良好的临床疗效。二氢卫矛醇（DAG）是一种治疗慢性髓性白血病和肺癌的化疗药物。最近，它已在胶质母细胞瘤治疗的 II 期临床试验中进行了测试；然而，DAG 在胶质母细胞瘤中的作用机制尚未阐明。在这里，我们表明 DAG 通过抑制基质金属蛋白酶-2（MMP2）的表达可以抑制 U251 细胞系的迁移和侵袭。此外，DAG 还可以抑制体外和斑马鱼模型中的肿瘤血管生成。机制研究表明，DAG 抑制了 VEGFR2 和 FGFR1 途径。我们的结果表明，DAG 可能是一种潜在的多靶标药物，可抑制肿瘤迁移、侵袭和血管生成，其抗血管生成作用可能涉及双重抑制 VEGF/VEGFR2 和 FGF2/FGFR1 信号通路。
