Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, Unites States of America.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, Unites States of America.
PLoS One. 2020 Mar 12;15(3):e0229801. doi: 10.1371/journal.pone.0229801. eCollection 2020.
We report the synthesis and preliminary characterization of IODVA1, a potent small molecule that is active in xenograft mouse models of Ras-driven lung and breast cancers. In an effort to inhibit oncogenic Ras signaling, we combined in silico screening with inhibition of proliferation and colony formation of Ras-driven cells. NSC124205 fulfilled all criteria. HPLC analysis revealed that NSC124205 was a mixture of at least three compounds, from which IODVA1 was determined to be the active component. IODVA1 decreased 2D and 3D cell proliferation, cell spreading and ruffle and lamellipodia formation through downregulation of Rac activity. IODVA1 significantly impaired xenograft tumor growth of Ras-driven cancer cells with no observable toxicity. Immuno-histochemistry analysis of tumor sections suggests that cell death occurs by increased apoptosis. Our data suggest that IODVA1 targets Rac signaling to induce death of Ras-transformed cells. Therefore, IODVA1 holds promise as an anti-tumor therapeutic agent.
我们报告了 IODVA1 的合成和初步表征，这是一种有效的小分子，在 Ras 驱动的肺癌和乳腺癌异种移植小鼠模型中具有活性。为了抑制致癌 Ras 信号，我们将计算机筛选与 Ras 驱动细胞的增殖和集落形成抑制相结合。NSC124205 满足了所有标准。HPLC 分析表明，NSC124205 是至少三种化合物的混合物，其中 IODVA1 被确定为活性成分。IODVA1 通过下调 Rac 活性，降低 2D 和 3D 细胞增殖、细胞铺展以及皱襞和片状伪足形成。IODVA1 显著抑制了 Ras 驱动的癌细胞的异种移植肿瘤生长，没有观察到毒性。肿瘤切片的免疫组织化学分析表明，细胞死亡是通过增加细胞凋亡发生的。我们的数据表明，IODVA1 靶向 Rac 信号通路诱导 Ras 转化细胞死亡。因此，IODVA1 有望成为一种抗肿瘤治疗剂。
