p53-independent structure-activity relationships of 3-ring mesogenic compounds' activity as cytotoxic effects against human non-small cell lung cancer lines.
p53-independent structure-activity relationships of 3-ring mesogenic compounds' activity as cytotoxic effects against human non-small cell lung cancer lines.
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DOI：
10.1186/s12885-016-2585-6
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发表时间：
2016-07-25
期刊：
影响因子：
3.8
通讯作者：
Kashiwakura I
中科院分区：
文献类型：
--
作者：
Fukushi S;Yoshino H;Yoshizawa A;Kashiwakura I
我们最近证明了液晶前体（下文称为“介晶化合物”）在携带野生型p53的人非小细胞肺癌（NSCLC）细胞系A549中的细胞毒性。在50%的NSCLC中观察到p53突变，并导致其对化疗的耐药性。为了开发更有效的癌症特异性药物，在这项研究中，我们研究了介晶化合物对多种NSCLC细胞具有细胞毒性作用的构效关系。在人NSCLC细胞（A549、LU 99、EBC-1和H1299）和正常WI-38人成纤维细胞中检查介晶化合物的药理学作用。进行细胞周期、细胞死亡诱导和衣壳蛋白酶表达的分析。具有末端烷基和羟基的3-环化合物（化合物C1-C5）在NSCLC细胞中显示出细胞毒性，而与p53状态无关。在核心中心具有嘧啶的化合物C1和C3诱导G2/M期阻滞，而没有嘧啶的化合物（C2、C4和C5）引起G1期阻滞;所有化合物产生半胱天冬酶介导的细胞死亡。这些事件以p53非依赖性方式发生。此外，表明化合物通过p53非依赖性DNA损伤信号通路诱导细胞死亡。化合物C2、C4和C5在WI-38细胞中没有显示出强的细胞毒性，而C1和C3显示出强的细胞毒性。然而，通过调节化合物的末端烷基链长度，化合物C1对WI-38细胞的细胞毒性得到改善。我们显示了与细胞毒性作用相关的介晶化合物的p53-独立的结构-活性关系。这些结构-活性关系将有助于开发更有效的癌症特异性药物。本文的在线版本（doi：10.1186/s12885-016-2585-6）包含补充材料，可供授权用户使用。
We recently demonstrated the cytotoxicity of liquid crystal precursors (hereafter referred to as “mesogenic compounds”) in the human non-small cell lung cancer (NSCLC) cell line A549 which carry wild-type p53. p53 mutations are observed in 50 % of NSCLC and contribute to their resistance to chemotherapy. To develop more effective and cancer-specific agents, in this study, we investigated the structure–activity relationships of mesogenic compounds with cytotoxic effects against multiple NSCLC cells. The pharmacological effects of mesogenic compounds were examined in human NSCLC cells (A549, LU99, EBC-1, and H1299) and normal WI-38 human fibroblast. Analyses of the cell cycle, cell-death induction, and capsases expression were performed. The 3-ring compounds possessing terminal alkyl and hydroxyl groups (compounds C1–C5) showed cytotoxicity in NSCLC cells regardless of the p53 status. The compounds C1 and C3, which possess a pyrimidine at the center of the core, induced G2/M arrest, while the compounds without a pyrimidine (C2, C4, and C5) caused G1 arrest; all compounds produced caspase-mediated cell death. These events occurred in a p53-independent manner. Furthermore, it was suggested that compounds induced cell death through p53-independent DNA damage-signaling pathway. Compounds C2, C4, and C5 did not show strong cytotoxicity in WI-38 cells, whereas C1 and C3 did. However, the cytotoxicity of compound C1 against WI-38 cells was improved by modulating the terminal alkyl chain lengths of the compound. We showed the p53-indepdent structure–activity relationships of mesogenic compounds related to the cytotoxic effects. These structure–activity relationships will be helpful in the development of more effective and cancer-specific agents. The online version of this article (doi:10.1186/s12885-016-2585-6) contains supplementary material, which is available to authorized users.