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首页> 外文期刊>Oncology Research >Inhibition of Carbonic Anhydrase IX by Ureidosulfonamide Inhibitor U104 Reduces Prostate Cancer Cell Growth, But Does Not Modulate Daunorubicin or Cisplatin Cytotoxicity
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Inhibition of Carbonic Anhydrase IX by Ureidosulfonamide Inhibitor U104 Reduces Prostate Cancer Cell Growth, But Does Not Modulate Daunorubicin or Cisplatin Cytotoxicity

机译：用ureidosulfonamide抑制剂U104抑制碳酸酐酶IX的抑制降低了前列腺癌细胞生长，但不调节大生霉素或顺铂细胞毒性

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摘要

Carbonic anhydrase (CA) IX has emerged as a promising target for cancer therapy. It is highly upregulated in hypoxic regions and mediates pH regulation critical for tumor cell survival as well as extracellular acidification of the tumor microenvironment, which promotes tumor aggressiveness via various mechanisms, such as augmenting metastatic potential. Therefore, the aim of this study was to analyze the complex interdependency between CA IX and the tumor microenvironment in prostate tumor cells with regard to potential therapeutic implications. CA IX was upregulated by hypoxia as well as acidosis in prostate cancer cells. This induction did not modulate intracellular pH but led to extracellular acidification. Pharmacological inhibition of CA IX activity by U104 (SLC-0111) resulted in a reduction in tumor cell growth and an increase in apoptotic cell death. Intracellular pH was reduced under normoxic and even more so under hypoxic conditions when CA IX level was high. However, although intracellular pH regulation was disturbed, targeting CA IX in combination with daunorubicin or cisplatin did not intensify apoptotic tumor cell death. Hence, targeting CA IX in prostate cancer cells can lead to intracellular pH dysregulation and, consequently, can reduce cellular growth and elevate apoptotic cell death. Attenuation of extracellular acidification by blocking CA IX might additionally impede tumor progression and metastasis. However, no beneficial effect was seen when targeting CA IX in combination with chemotherapeutic drugs.
机译：碳酸酐酶（CA）IX已成为癌症治疗的有希望的靶标。它在缺氧区域中高度上调，介导对肿瘤细胞存活的pH调节以及肿瘤微环境的细胞外酸化，这通过各种机制促进肿瘤侵袭性，例如增强转移性潜力。因此，该研究的目的是分析Ca IX与肿瘤微环境之间的复杂相互依赖性，在前列腺肿瘤细胞中的潜在治疗意义。 Ca IX被缺氧以及前列腺癌细胞中的酸中毒上调。这种诱导没有调节细胞内pH，但导致细胞外酸化。 U104（SLC-0111）的Ca IX活性的药理抑制导致肿瘤细胞生长降低和凋亡细胞死亡的增加。当Ca IX水平高时，在常氧的常氧甚至更加下细胞内pH甚至更加降低。然而，尽管细胞内pH调节受到干扰，但靶向Ca Ix与Daunorubicin或顺铂组合并未加剧凋亡肿瘤细胞死亡。因此，靶向前列腺癌细胞中的CaIX可以导致细胞内pH失调，因此可以降低细胞生长并提高凋亡细胞死亡。通过阻断Ca Ix衰减细胞外酸化可以妨碍肿瘤进展和转移。然而，当将CAIX与化学治疗药物组合靶向CA IX时，没有看到有益效果。

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  • 来源
    《Oncology Research》 |2018年第2期|共10页
  • 作者

    Riemann Anne; Guettler Antje; Haupt Verena; Wichmann Henri; Reime Sarah; Bache Matthias; Vordermark Dirk; Thews Oliver;

  • 作者单位

    Univ Halle Wittenberg Julius Bernstein Inst Physiol Magdeburger Str 6 D-06112 Halle Germany;

    Univ Halle Wittenberg Klin &

    Poliklin Strahlentherapie Halle Germany;

    Univ Halle Wittenberg Julius Bernstein Inst Physiol Magdeburger Str 6 D-06112 Halle Germany;

    Univ Halle Wittenberg Klin &

    Poliklin Strahlentherapie Halle Germany;

    Univ Halle Wittenberg Julius Bernstein Inst Physiol Magdeburger Str 6 D-06112 Halle Germany;

    Univ Halle Wittenberg Klin &

    Poliklin Strahlentherapie Halle Germany;

    Univ Halle Wittenberg Klin &

    Poliklin Strahlentherapie Halle Germany;

    Univ Halle Wittenberg Julius Bernstein Inst Physiol Magdeburger Str 6 D-06112 Halle Germany;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

    Carbonic anhydrase IX (CA IX); Acidosis; Intracellular pH; Cytotoxicity;

    机译：碳酸酐酶IX（CA IX）;酸中毒;细胞内pH;细胞毒性;

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