Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis‐inducing ability
Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis‐inducing ability
复制标题
DOI：
10.1002/ijc.25048
复制
发表时间：
2010-07
影响因子：
6.4
通讯作者：
Ying-yi Li;Ying‐Ying Wang;T. Taniguchi;T. Kawakami;T. Baba;H. Ishibashi*;N. Mukaida
中科院分区：
文献类型：
--
作者：
Ying-yi Li;Ying‐Ying Wang;T. Taniguchi;T. Kawakami;T. Baba;H. Ishibashi*;N. Mukaida
我们先前证明，Pim-3是一种具有丝氨酸/苏氨酸激酶活性的原癌基因，在恶性病变中异常表达，但在内胚层衍生器官的正常组织中不表达，包括胰腺、肝脏、结肠和胃。此外，异常表达的Pim‐3可以通过灭活促凋亡分子Bad和增强抗凋亡分子Bcl‐XL的表达来防止肿瘤细胞凋亡。这些观察结果促使我们推测，靶向Pim-3激酶的化学物质可能是新型抗癌药物的良好候选者。因此，我们通过检查它们在体外抑制Pim-3激酶活性的能力来筛选各种低分子化合物。我们观察到一些合成的百部酰胺中间体可以抑制Pim-3激酶及其相关激酶的体外活性，如Pim-1和Pim-2。此外，这些化合物抑制各种人胰腺癌、肝细胞癌和结肠癌细胞系的体外细胞增殖。此外，所述化合物可以通过减少磷酸化-Ser 112-Bad的量而不是Bad和Pim-3的总量来体外诱导人胰腺癌细胞系的凋亡。最后，当将该化合物给予注射人胰腺癌细胞系的裸鼠时，它通过增加凋亡细胞数量和减少增殖细胞数量来延缓肿瘤生长，而不会对血细胞计数造成严重的不良影响。这些观察结果表明，化学品及其相关化合物可能有效治疗内胚层来源器官的肿瘤，特别是胰腺。
We previously demonstrated that Pim‐3, a protooncogene with serine/threonine kinase activity, was aberrantly expressed in malignant lesions but not in normal tissues of endoderm‐derived organs, including pancreas, liver, colon and stomach. Moreover, aberrantly expressed Pim‐3 can prevent tumor cell apoptosis by inactivating a proapoptotic molecule, Bad, and enhancing the expression of an antiapoptotic molecule, Bcl‐XL. These observations prompted us to speculate that a chemical targeting Pim‐3 kinase may be a good candidate for a novel type of anticancer drug. Hence, we screened various low‐molecule compounds by examining their capacity to inhibit Pim‐3 kinase activity in vitro. We observed that some synthetic intermediates of stemonamide can inhibit in vitro activities of Pim‐3 kinase and its related kinases, such as Pim‐1 and Pim‐2. Moreover, these compounds inhibit in vitro cell proliferation of various human pancreatic, hepatocellular and colon cancer cell lines. Furthermore, the compounds can induce apoptosis of human pancreatic cancer cell lines in vitro by reducing the amount of phospho‐Ser112‐Bad, but not total amounts of Bad and Pim‐3. Finally, when the compound was administered to nude mice injected with a human pancreatic cancer cell line, it retarded tumor growth by increasing apoptotic cell numbers and decreasing proliferating cell numbers without causing serious adverse effects on blood counts. These observations indicate that the chemicals and its related compounds may be effective for the treatment of tumors of endoderm‐derived organs, particularly the pancreas.