Disrupting polyamine homeostasis as a therapeutic strategy for neuroblastoma.
Disrupting polyamine homeostasis as a therapeutic strategy for neuroblastoma.
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DOI：
10.1158/1078-0432.ccr-08-3213
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发表时间：
2009-10-01
期刊：
影响因子：
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通讯作者：
Hogarty MD
中科院分区：
文献类型：
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作者：
Evageliou NF;Hogarty MD
MYC基因在多种人类癌症中不受调控。通过直接和间接的机制，MYC网络调节了人类基因组中b> 15%的表达，包括蛋白质编码rna和非编码rna。这种复杂性使得定义介导MYC致癌活性的主要途径的努力复杂化。MYC在提供增殖细胞的生物能量和生物量需求方面发挥着核心作用，而多胺是支持许多这些功能的基本细胞成分。多胺生物合成中的限速酶ODC是MYC的真正靶标，这一途径中的其他调节酶也是如此。大量数据表明，多胺生物合成与癌症进展有关，而多胺耗竭可能限制肿瘤前病变的恶性转化。使用转基因癌症模型的研究也支持MYC对肿瘤发生和发展的影响可以通过抑制多胺的产生而减弱。高风险神经母细胞瘤（通常是致命的胚胎肿瘤，MYC的激活是最重要的）解除对许多多胺酶的调节，促进细胞内多胺池的扩大。在临床前模型中，选择性抑制该途径中的关键酶，例如使用DFMO和/或SAM486，可减少肿瘤发生并与化疗协同作用以使肿瘤消退。在这里，我们回顾了这些和其他多胺消耗药物在神经母细胞瘤和其他MYC手术的晚期癌症中的潜在临床应用。
MYC genes are deregulated in a plurality of human cancers. Through direct and indirect mechanisms the MYC network regulates the expression of >15% of the human genome, including both protein-coding and non-coding RNAs. This complexity has complicated efforts to define the principal pathways mediating MYC’s oncogenic activity. MYC plays a central role providing for the bioenergetic and biomass needs of proliferating cells, and polyamines are essential cell constituents supporting many of these functions. The rate-limiting enzyme in polyamine biosynthesis, ODC, is a bona fide MYC target, as are other regulatory enzymes in this pathway. A wealth of data link enhanced polyamine biosynthesis to cancer progression, and polyamine-depletion may limit malignant transformation of pre-neoplastic lesions. Studies using transgenic cancer models also supports that the effect of MYC on tumor initiation and progression can be attenuated through repression of polyamine production. High-risk neuroblastomas (an often lethal embryonal tumor in which MYC activation is paramount) deregulate numerous polyamine enzymes to promote expansion of intracellular polyamine pools. Selective inhibition of key enzymes in this pathway, e.g., using DFMO and/or SAM486, reduces tumorigenesis and synergizes with chemotherapy to regress tumors in pre-clinical models. Here we review the potential clinical application of these and additional polyamine-depletion agents to neuroblastoma and other advanced cancers in which MYC is operative.