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首页> 外文学位 >Briciclib (on 013105), an elF4E inhibitor, exhibits potent anti-cancer activity in various preclinical cancer models.
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Briciclib (on 013105), an elF4E inhibitor, exhibits potent anti-cancer activity in various preclinical cancer models.

机译：elF4E抑制剂Briciclib（在013105上）在各种临床前癌症模型中均显示出强大的抗癌活性。

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摘要

Introduction: Eukaryotic translation initiation factor 4E (e1F4E) is a proto-oncogene that regulates protein synthesis by facilitating translation of mRNA in mammalian cells. eIF4E promotes translation of several potent oncogenic genes, including (Cyclin D1 and c-Myc) that further induce cellular growth and proliferation. Overexpression of eIF4E and its downstream targets (Cyclin D1 and c-Myc) has been associated with various human malignancies. Therefore, targeting of eIF4E with a selective inhibitor could aid in development of novel therapeutic regimen(s) for treatment of different types of cancer. Briciclib (ON 013105) is one such pre-clinical eIF4E inhibitor developed by Onconova Therapeutics Inc. In this study we investigated the anti-cancer activity of briciclib in various in vitro models of mantle cell lymphoma (MCL) breast cancer. In addition, we also determined the expression of eIF4E downstream targets (Cyclin DI and c-Myc) and apoptotic markers (P53, Cleaved Caspase 3 and Cleaved PARP) after treatment with briciclib.;Methods: MTT cell viability assay was performed to evaluate cellular viability after treatment with briciclib. Expression for the downstream targets of eIF4E (Cyclin D1 and c-Myc) was analyzed using western blot analysis and confirmed quantitatively with ELISA. Long term inhibitory effect of briciclib in MCL and breast cancer cell lines was examined with washout experiments and cell survival assays respectively. DNA fragmentation assay was performed to evaluate late stage apoptosis. Furthermore, cell cycle analyses were done to analyze the effect of briciclib on cell cycle progression in both MCL and breast cancer cells.;Results: The cell viability assay data indicate that briciclib treatment significantly reduced proliferation of MCL (JeKo-1 and M1NO) and breast (MCF7 and MDA-MB-231) cancer cell lines. The protein expression data showed that treatment with briciclib suppressed the expression of both Cyclin Dl and c-Myc in breast and MCL cancer cell lines. These observations were further supported by quantitative analysis of Cyclin Dl and c-Myc protein levels with ELISA. Moreover, treatment with briciclib enhanced the expression of pro-apoptotic proteins in MCL and breast cancer cell lines. Results from cell cycle analyses confirmed that briciclib showed significant increase in GO phase (accounts for cell death) for JeKo-1 cells and G2/M phase (accounts for mitotic arrest) for MCF7 cells.;Conclusion: Overall results emphasize the potential of briciclib, an oral eIF4 inhibitor, in treating hematopoietic and solid cancers. Briciclib is a promising anti-cancer agent that showed potent inhibitory effect in various MCL and breast cancer models, in vitro. Further characterization of various briciclib oral formulations in in vivo models of MCL and breast cancer is essential to bring this pre-clinical eIF4E inhibitor from bench-side to bed-side.
机译：简介：真核翻译起始因子4E（e1F4E）是一种原癌基因，通过促进哺乳动物细胞中mRNA的翻译来调节蛋白质的合成。 eIF4E促进几种有效的致癌基因的翻译，包括（Cyclin D1和c-Myc），这些基因进一步诱导细胞生长和增殖。 eIF4E及其下游靶标（Cyclin D1和c-Myc）的过表达与各种人类恶性肿瘤有关。因此，用选择性抑制剂靶向eIF4E可以有助于开发新的治疗方案来治疗不同类型的癌症。 Briciclib（ON 013105）是Onconova Therapeutics Inc.开发的一种此类临床前eIF4E抑制剂。在这项研究中，我们研究了briciclib在套细胞淋巴瘤（MCL）乳腺癌的各种体外模型中的抗癌活性。此外，我们还确定了briciclib处理后eIF4E下游靶标（Cyclin DI和c-Myc）和凋亡标记物（P53，Cleaved Caspase 3和Cleaved PARP）的表达。方法：进行MTT细胞活力测定以评估细胞Briciclib治疗后的生存力。使用蛋白质印迹分析分析eIF4E下游靶标（Cyclin D1和c-Myc）的表达，并通过ELISA进行定量确认。 Briciclib在MCL和乳腺癌细胞系中的长期抑制作用分别通过洗脱实验和细胞存活试验进行了检验。进行DNA片段化分析以评估晚期细胞凋亡。此外，进行细胞周期分析以分析briciclib对MCL和乳腺癌细胞的细胞周期进程的影响。结果：细胞生存力检测数据表明briciclib治疗显着降低了MCL（JeKo-1和M1NO）的增殖，并且乳腺癌（MCF7和MDA-MB-231）癌细胞系。蛋白质表达数据表明，briciclib处理可抑制乳腺癌和MCL癌细胞系中Cyclin D1和c-Myc的表达。通过ELISA对Cyclin D1和c-Myc蛋白水平的定量分析进一步支持了这些观察结果。而且，用briciclib治疗增强了MCL和乳腺癌细胞系中促凋亡蛋白的表达。细胞周期分析的结果证实，briciclib对JeKo-1细胞的GO期（导致细胞死亡）和MCF7细胞的G2 / M期（有丝分裂阻滞）具有显着增加。结论：总体结果强调了briciclib的潜力，一种口服eIF4抑制剂，用于治疗造血和实体癌。 Briciclib是一种有前途的抗癌药，在多种MCL和乳腺癌模型中均显示出有效的抑制作用。在MCL和乳腺癌的体内模型中进一步表征各种briciclib口服制剂对于将这种临床前eIF4E抑制剂从实验台推向临床很重要。

著录项

  • 作者

    Desai, Bina.;

  • 作者单位

    Long Island University, The Brooklyn Center.;

  • 授予单位 Long Island University, The Brooklyn Center.;
  • 学科 Pharmacology.;Cellular biology.
  • 学位 M.S.
  • 年度 2015
  • 页码 74 p.
  • 总页数 74
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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