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Activation of tumor cell death program by targeting the ubiquitin-proteasome pathway: Significance in cancer treatment and prevention.

机译：通过靶向泛素-蛋白酶体途径激活肿瘤细胞死亡程序：在癌症治疗和预防中的意义。

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摘要

The ubiquitin-proteasome pathway serves as a quality control mechanism to regulate the degradation of intracellular proteins involved in a wide array of cellular processes including tumorigeneis. Thus targeting key features of protein turnover responsible for the growth and proliferation of cancer have emerged as a favorable approach in cancer therapy. Both in vitro and in vivo experimental and clinical results have demonstrated the potential use of proteasome inhibitors as novel anticancer drugs. The widespread clinical success of platinum-containing drugs served as a catalyst for investigating other metal complexes for the treatment of human cancer. In an effort to improve upon the limitations of platinum anticancer drugs, different metals and metal complexes that pose different mechanisms of action has been investigated as potential anticancer drugs. We have previously found that different metal containing complexes, including those of copper, zinc, gold, and tin could activate tumor cell death by inhibiting the proteasome. Therefore, it is proposed that gallium could similarly act as a proteasome inhibitor and apoptosis inducer in human tumor cells. The data presented in this dissertation strongly supports this hypothesis. We found that gallium-cotaining [NN'O] tridentate ligands appended with halogen substituents could inhibit the proteasomal activity in vitro and in human prostate cancer cells. Importantly, the most biologically active complex (5) could inhibit tumor growth in mice-bearing prostate cancer xenografts associated with inhibition of proteasomal activity and apoptosis. Based on the favorable cytotoxic activity of [NN'O] ligands complexed with gallium, subsequent studies relied on this model architecture complexed to different bivalent transistion metals to gain insight into the pharmacophore responsible for their proteasome-inhibitory effects. Since elevated levels of copper are a trademark of many tumors, targeting heightened levels of copper with copper-binding compounds as a means of tumor growth ablation was proposed. It was found that that these copper complexes (1-3), with distinct stoichiometries and protonation states, acted as proteasome inhibitiors and apoptosis inducers in cultured prostate cancer cells, and importantly the species [CuL I]+ as the minimal pharmacophore responsible for this effect. This hypothesis was further substantiated by the finding that Zinc-containing [NN'O] complex (2), but not Nickel (1) could inhibit the proteasomal activity of a purified 20S proteasome and culture prostate cancer cells associated with massive tumor cell death. These results strengthen our current working hypothesis that fast ligand dissociation (Zn-complex) is required to free up the [MLIA]+ capable of interaction with the proteasome. This is in agreement with previous studies showing that proteasome inhibition by zinc-containing dithiocarbamate derivatives is associated with apoptosis induction. In contrast, chapters 5 and 6 were primarily focused on the mechanistic properties of proteasome inhibition and its downstream events. Since we have previously reported on a gold(III) complex showing potent in vitro and in vivo growth inhibitory activity associated with proteasome inhibition and apoptosis, two gold compounds that differ in the oxidation state of the metal were investigated to gain mechanistic insight into their biological activities. The data in this dissertation provides compelling evidence for the involvement of ROS-mediated proteasome inhibition by gold(III), but not gold(I), and highlights distinct mechanisms of action associated with their biological effects. Since it has been shown that proteasome inhibition is tightly linked to apoptosis in AR (+) prostate cancer cells, it is proposed that AR can influence the regulatory events associated with cell death in prostate cancer cells. Mechanistic studies from chapter 6 provide convincing evidence that proteasome inhibitor- or chemotherapy- induced cell death resulted in significantly higher levels of caspase-3 activity in AR independent prostate cancer cells compared to stably or transiently expressing AR cells. Interestingly, lower levels of caspase 3 activity were partially reversed with the addition of an AR antagonist in AR-dependent prostate cancer cells. These important findings could help facilitate the design of novel therapeutic strategies in the treatment of prostate cancer. Taken together, the studies presented in this dissertation could hold tremendous prognostic and therapeutic potential in the treatment of human cancer.
机译：泛素-蛋白酶体途径用作质量控制机制，以调节参与包括肿瘤发生在内的各种细胞过程的细胞内蛋白质的降解。因此，针对负责癌症生长和增殖的蛋白质更新的关键特征已经成为癌症治疗中的一种有利方法。体外和体内实验及临床结果均证明了蛋白酶体抑制剂作为新型抗癌药物的潜在用途。含铂药物在临床上获得了广泛的成功，成为研究其他金属配合物治疗人类癌症的催化剂。为了改善铂类抗癌药的局限性，已研究了具有不同作用机理的不同金属和金属络合物作为潜在的抗癌药。我们以前已经发现，不同的含金属的配合物，包括铜，锌，金和锡的配合物，可以通过抑制蛋白酶体来激活肿瘤细胞的死亡。因此，提出镓可以类似地在人肿瘤细胞中充当蛋白酶体抑制剂和凋亡诱导剂。本文提出的数据有力地支持了这一假设。我们发现，含卤素取代基的含镓[NN'O]三齿配体可在体外和人前列腺癌细胞中抑制蛋白酶体活性。重要的是，最具生物活性的复合物（5）可以抑制荷瘤前列腺癌异种移植物中肿瘤的生长，这与抑制蛋白酶体活性和凋亡有关。基于与镓复合的[NN'O]配体的良好细胞毒性活性，后续研究依赖于与不同的二价金属离子复合的这种模型结构，以深入了解负责其蛋白酶体抑制作用的药效团。由于升高的铜水平是许多肿瘤的标志，因此提出了以铜结合化合物靶向升高的铜水平作为肿瘤生长消融的手段。已发现这些铜配合物（1-3）具有不同的化学计量比和质子化状态，在培养的前列腺癌细胞中充当蛋白酶体抑制剂和凋亡诱导剂，重要的是，物种[CuL I] +是造成这种情况的最小药效团。影响。通过发现含锌的[NN'O]复合物（2）而不是镍（1）可以抑制纯化的20S蛋白酶体和培养的前列腺癌细胞的蛋白酶体活性，从而证实该假说与大规模肿瘤细胞死亡有关，从而进一步证实了这一假设。这些结果加强了我们当前的工作假设，即需要快速的配体解离（Zn-络合物）以释放能够与蛋白酶体相互作用的[MLIA] +。这与先前的研究一致，后者表明含锌的二硫代氨基甲酸酯衍生物对蛋白酶体的抑制与细胞凋亡的诱导有关。相比之下，第5章和第6章主要集中在蛋白酶体抑制及其下游事件的机理上。由于我们先前曾报道过一种金（III）配合物，显示出与蛋白酶体抑制和细胞凋亡相关的有效的体外和体内生长抑制活性，因此对两种金属氧化态不同的金化合物进行了研究，以对其生物机理进行深入的研究。活动。本论文中的数据提供了有力的证据证明金（III）参与了ROS介导的蛋白酶体抑制，但金（I）没有参与，并突出了与其生物学效应相关的独特作用机制。由于已经显示蛋白酶体的抑制作用与AR（+）前列腺癌细胞的凋亡紧密相关，因此提出AR可以影响与前列腺癌细胞中细胞死亡相关的调节事件。第六章的机理研究提供了令人信服的证据，与稳定或短暂表达的AR细胞相比，蛋白酶体抑制剂或化学疗法诱导的细胞死亡导致AR独立的前列腺癌细胞中caspase-3活性水平显着提高。有趣的是，在AR依赖型前列腺癌细胞中加入AR拮抗剂后，caspase 3活性的降低部分被逆转。这些重要发现可以帮助促进前列腺癌治疗中新治疗策略的设计。综上所述，本文提出的研究可以在人类癌症的治疗中具有巨大的预后和治疗潜力。

著录项

  • 作者

    Frezza, Michael.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Biology Molecular.Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 289 p.
  • 总页数 289
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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