Kovacevic Zaklina, Richardson Des R
Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
Carcinogenesis. 2006 Dec;27(12):2355-66. doi: 10.1093/carcin/bgl146. Epub 2006 Aug 18.
Tumor metastasis is an important clinical problem, contributing to the majority of cancer-related deaths. The recent discovery of metastasis suppressor genes, such as N-myc downstream-regulated gene-1 (Ndrg-1), has introduced a novel approach to treating cancer and preventing metastasis. Ndrg-1 has been identified as a protein involved in the differentiation of epithelial cells. In addition, Ndrg-1 expression can be regulated by androgens and is involved in the pathology of the disease, Hereditary Motor and Sensory Neuropathy-Lom (HMSNL). However, one of the most well documented links between Ndrg-1 and pathophysiology is its association with inhibition of tumor metastasis. The expression of Ndrg-1 was found to be significantly downregulated in a variety of different neoplasms including breast, colon and prostate cancer. Furthermore, Ndrg-1 expression was shown to be negatively correlated with tumor metastasis. Studies in vitro and in vivo have demonstrated a significant reduction in the metastatic ability of cells overexpressing Ndrg-1. The ability of these cells to invade was also compromised. The Gleason grade of prostate and breast cancers was found to correlate with Ndrg-1 expression, with more advanced and poorly differentiated tumors having lower Ndrg-1 levels. Recently, Ndrg-1 expression was demonstrated to be regulated by cellular iron levels and induced by iron chelators. These latter compounds were recently identified as potential anticancer agents as they selectively prevent cancer cell proliferation and lead to apoptosis. The discovery that iron chelators also increase Ndrg-1 expression further augments their antitumor activity and provides a novel strategy for the treatment of cancer and its metastasis.
肿瘤转移是一个重要的临床问题，导致了大多数与癌症相关的死亡。最近转移抑制基因的发现，如N - myc下游调控基因1（Ndrg - 1），为癌症治疗和预防转移引入了一种新方法。Ndrg - 1已被确定为一种参与上皮细胞分化的蛋白质。此外，Ndrg - 1的表达可受雄激素调节，并参与遗传性运动和感觉神经病 - 洛姆（HMSNL）疾病的病理过程。然而，Ndrg - 1与病理生理学之间最有充分记录的联系之一是其与抑制肿瘤转移的关联。在包括乳腺癌、结肠癌和前列腺癌在内的多种不同肿瘤中，发现Ndrg - 1的表达显著下调。此外，Ndrg - 1的表达与肿瘤转移呈负相关。体外和体内研究表明，过表达Ndrg - 1的细胞转移能力显著降低。这些细胞的侵袭能力也受到损害。发现前列腺癌和乳腺癌的Gleason分级与Ndrg - 1表达相关，肿瘤越晚期且分化差，Ndrg - 1水平越低。最近，证明Ndrg - 1的表达受细胞铁水平调节，并由铁螯合剂诱导。这些化合物最近被确定为潜在的抗癌剂，因为它们选择性地阻止癌细胞增殖并导致细胞凋亡。铁螯合剂还能增加Ndrg - 1表达这一发现进一步增强了它们的抗肿瘤活性，并为癌症及其转移的治疗提供了一种新策略。
