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首页> 外文期刊>Molecular cancer therapeutics >6 alpha-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells
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6 alpha-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells

机译：6α-乙酰氧基韦替肽：一种新型结构类别的有丝分裂抑制剂，破坏前列腺癌细胞中的微管动态

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The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6 alpha-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects, and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA-treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared with the anticancer drug vinblastine, which included pathways involved in mitosis, microtubule spindle organization, and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced cellular microtubule polymer mass. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids (vinblastine/vincristine) or 2-methoxyestradiol did not confer resistance to 6-AA, suggesting a different mechanism of microtubule interaction. 6-AA is a first-in-class microtubule inhibitor that features the unique anopterine scaffold. This study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease. (C) 2016 AACR.
机译：缺乏用于转移性阉割的前列腺癌（MCRPC）突出迫切需要更有效的药物来对抗这种疾病。在此，我们报告了前列腺癌细胞中天然产物6α-乙酰氧基替尼（6-AA）的作用机制。在低纳米摩尔剂量，这种来自澳大利亚流域的常毒性生物碱anopterus macleayanus诱导LNCAP和PC3（前列腺癌）细胞的强烈积累以及有丝分裂，严重有丝分裂的主轴缺陷和不对称细胞分部的HeLa（宫颈癌）细胞，最终导致有丝分裂灾难通过细胞凋亡伴有细胞死亡。与途径分析相结合的6-AA处理的LNCAP细胞的DNA微阵列鉴定了与抗癌药物致疱疹的抗分炎，微管纺织组织和微管结合的途径相比具有非常相似的转录变化。与长春细胞一样，6-AA抑制无细胞系统中的微管聚合并降低细胞微管聚合物质量。然而，与抗衰退的微管稳定性药物（如vinca生物碱（长鸟类/长春酮）或2-甲氧基雌二醇等抗性的微管改变没有赋予6-AA的抗性，表明微管相互作用的不同机制。 6-AA是一类级别的微管抑制剂，具有独特的绕线支架。本研究提供了强烈的理由，以进一步开发这种新型结构类别的微管抑制剂，用于治疗恶性疾病。 （c）2016 AACR。

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  • 来源
    《Molecular cancer therapeutics》 |2017年第1期|共13页
  • 作者

    Levrier Claire; Sadowski Martin C.; Rockstroh Anja; Gabrielli Brian; Kavallaris Maria; Lehman Melanie; Davis Rohan A.; Nelson Colleen C.;

  • 作者单位

    Queensland Univ Technol Australian Prostate Canc Res Ctr Queensland Inst Hlth &

    Biomed Innovat;

    Queensland Univ Technol Australian Prostate Canc Res Ctr Queensland Inst Hlth &

    Biomed Innovat;

    Queensland Univ Technol Australian Prostate Canc Res Ctr Queensland Inst Hlth &

    Biomed Innovat;

    Univ Queensland Diamantina Inst Translat Res Inst Brisbane Qld Australia;

    Univ New South Wales Australia Lowy Canc Res Ctr Childrens Canc Inst Tumour Biol &

    Targeting;

    Queensland Univ Technol Australian Prostate Canc Res Ctr Queensland Inst Hlth &

    Biomed Innovat;

    Griffith Univ Eskitis Inst Drug Discovery Brisbane Qld Australia;

    Queensland Univ Technol Australian Prostate Canc Res Ctr Queensland Inst Hlth &

    Biomed Innovat;

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  • 正文语种 eng
  • 中图分类 肿瘤学;
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