A Synthetic Podophyllotoxin Derivative Exerts Anti-Cancer Effects by Inducing Mitotic Arrest and Pro-Apoptotic ER Stress in Lung Cancer Preclinical Models
A Synthetic Podophyllotoxin Derivative Exerts Anti-Cancer Effects by Inducing Mitotic Arrest and Pro-Apoptotic ER Stress in Lung Cancer Preclinical Models
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DOI：
10.1371/journal.pone.0066841
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发表时间：
2013-04-30
期刊：
影响因子：
3.7
通讯作者：
Wang, Yi-Ching
中科院分区：
文献类型：
--
作者：
Chen, Jia-Yang;Tang, Yen-An;Wang, Yi-Ching
从天然植物中提取的微管蛋白结合剂，如鬼臼毒素、紫杉醇等已被开发出来。然而，细胞毒选择性差，严重的副作用和有限的有效性仍然是其治疗应用的主要问题。我们开发了一种全合成的鬼臼毒素衍生物Ching 001，并在肺癌临床前模型中研究了其抗肿瘤生长的作用和机制。Ching 001对不同的肺癌细胞株有选择性的细胞毒作用，但对正常肺细胞无明显的细胞毒作用。Ching 001抑制微管的聚合，导致有丝分裂停滞，如有丝分裂相关蛋白、生存素和极光B的积累，从而导致DNA损伤和凋亡。Ching 001还激活促凋亡ER应激信号通路。实验转移试验中，腹腔注射2 mg/kg Ching 001可明显抑制A549异种移植瘤的生长，而注射0.2 mg/kg Ching 001可降低A549细胞的肺定植能力。这些抗肿瘤生长和肺定植抑制作用强于相同剂量的紫杉醇治疗。异种移植瘤组织染色进一步证实Ching 001诱导有丝分裂阻滞和肿瘤凋亡。此外，血液学和血液生化学检查以及组织检查表明，Ching 001治疗在受试动物中未显示出明显的器官毒性。我们提供的临床前证据表明，新型合成微管抑制剂Ching 001，它可以通过诱导有丝分裂阻滞和ER应激引发DNA损伤和凋亡，是一种潜在的抗癌化合物，可用于进一步的药物开发。
Some potent chemotherapy drugs including tubulin-binding agents had been developed from nature plants, such as podophyllotoxin and paclitaxel. However, poor cytotoxic selectivity, serious side-effects, and limited effectiveness are still the major concerns in their therapeutic application. We developed a fully synthetic podophyllotoxin derivative named Ching001 and investigated its anti-tumor growth effects and mechanisms in lung cancer preclinical models. Ching001 showed a selective cytotoxicity to different lung cancer cell lines but not to normal lung cells. Ching001 inhibited the polymerization of microtubule resulting in mitotic arrest as evident by the accumulation of mitosis-related proteins, survivin and aurora B, thereby leading to DNA damage and apoptosis. Ching001 also activated pro-apoptotic ER stress signaling pathway. Intraperitoneal injection of 2 mg/kg Ching001 significantly inhibited the tumor growth of A549 xenograft, while injection of 0.2 mg/kg Ching001 decreased the lung colonization ability of A549 cells in experimental metastasis assay. These anti-tumor growth and lung colonization inhibition effects were stronger than those of paclitaxel treatment at the same dosage. The xenograft tumor tissue stains further confirmed that Ching001 induced mitosis arrest and tumor apoptosis. In addition, the hematology and biochemistry tests of blood samples as well as tissue examinations indicated that Ching001 treatment did not show apparent organ toxicities in tested animals. We provided preclinical evidence that novel synthetic microtubule inhibitor Ching001, which can trigger DNA damage and apoptosis by inducing mitotic arrest and ER stress, is a potential anti-cancer compound for further drug development.