Novel Thiosemicarbazone Iron Chelators Induce Up-Regulation and Phosphorylation of the Metastasis Suppressor N-myc Down-Stream Regulated Gene 1: A New Strategy for the Treatment of Pancreatic Cancer
Novel Thiosemicarbazone Iron Chelators Induce Up-Regulation and Phosphorylation of the Metastasis Suppressor N-myc Down-Stream Regulated Gene 1: A New Strategy for the Treatment of Pancreatic Cancer
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DOI：
10.1124/mol.111.073627
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发表时间：
2011-10-01
影响因子：
3.6
通讯作者：
Richardson, Des R.
中科院分区：
文献类型：
--
作者：
Kovacevic, Zaklina;Chikhani, Sherin;Richardson, Des R.
胰腺癌是一种侵袭性肿瘤，死亡率接近100%。最成功的胰腺癌治疗药物是吉西他滨，尽管在患者生存方面的总体效果仍然非常差。本研究的目的是评价一类新的抗胰腺癌的抗癌药物。这组化合物属于联吡啶缩氨基硫脲类，已显示其在体外和体内对一系列不同肿瘤具有有效和选择性活性。我们首次在胰腺癌中证明，这些药物增加了生长和转移抑制因子N-myc下游调节基因1的表达及其在Ser 330和Thr 346的磷酸化，这对其抗肿瘤活性至关重要。此外，这些药物增加胰腺癌细胞中细胞周期蛋白依赖性激酶抑制剂p21（CIP 1/WAF 1）的表达，而减少细胞周期蛋白D1。总之，这些分子改变部分解释了观察到的显著抗肿瘤活性。事实上，这些药物的体外抗增殖活性显著高于已建立的胰腺癌治疗方法，即吉西他滨和5-氟尿嘧啶。体内研究表明，一种新的缩氨基硫脲，即二-2-吡啶基酮4-环己基-4-甲基-3-缩氨基硫脲盐酸盐，完全抑制胰腺癌异种移植物的生长，没有证据表明正常组织组织学的显着改变。总之，我们的研究已经确定了一种新的和有效的抗肿瘤药物，可能是有用的胰腺癌治疗的分子效应。
Pancreatic cancer is an aggressive neoplasm, with a mortality rate close to 100%. The most successful agent for pancreatic cancer treatment is gemcitabine, although the overall effect in terms of patient survival remains very poor. This study was initiated to evaluate a novel class of anticancer agents against pancreatic cancer. This group of compounds belongs to the dipyridyl thiosemicarbazone class that have been shown to have potent and selective activity against a range of different neoplasms in vitro and in vivo. We demonstrate for the first time in pancreatic cancer that these agents increase the expression of the growth and metastasis suppressor N-myc downstream-regulated gene 1 and its phosphorylation at Ser330 and Thr346 that is important for its activity against this tumor. In addition, these agents increased expression of the cyclin-dependent kinase inhibitor p21(CIP1/WAF1), whereas decreasing cyclin D1 in pancreatic cancer cells. Together, these molecular alterations account, in part, for the pronounced antitumor activity observed. Indeed, these agents had significantly higher antiproliferative activity in vitro than the established treatments for pancreatic cancer, namely gemcitabine and 5-fluorouracil. Studies in vivo demonstrated that a novel thiosemicarbazone, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride, completely inhibited the growth of pancreatic cancer xenografts with no evidence of marked alterations in normal tissue histology. Together, our studies have identified molecular effectors of a novel and potent antitumor agent that could be useful for pancreatic cancer treatment.