Targeting pro-invasive oncogenes with short chain fatty acid-hexosamine analogues inhibits the mobility of metastatic MDA-MB-231 breast cancer cells.
Targeting pro-invasive oncogenes with short chain fatty acid-hexosamine analogues inhibits the mobility of metastatic MDA-MB-231 breast cancer cells.
复制标题
DOI：
10.1021/jm800873k
复制
发表时间：
2008-12-25
影响因子：
7.3
通讯作者：
Yarema KJ
中科院分区：
文献类型：
--
作者：
Campbell CT;Aich U;Weier CA;Wang JJ;Choi SS;Wen MM;Maisel K;Sampathkumar SG;Yarema KJ
全丁酰化N-乙酰基-d-甘露糖胺（Bu 4 ManNAc）是一种SCFA-己糖胺癌症候选药物，其活性通过完整的正丁酸酯-碳水化合物键表现出来，与全丁酰化-d-甘露糖（Bu 5 Man）不同，它减少了转移性MDA-MB-231乳腺癌细胞的侵袭，而全丁酰化-d-甘露糖（Bu 5 Man）是一种临床测试的化合物，不会改变细胞的移动性。为了获得分子水平的洞察力，研究了与转移有关的治疗靶点。活性化合物Bu 4 ManNAc降低MUC 1表达和MMP-9活性（通过下调CXCR 4转录），而“非活性”Bu 5 Man对这些癌基因具有平衡作用。这种对转录的不同影响与HDACi活性（由Bu 4 ManNAc和Bu 5 Man保持）和NF-κB活性之间的相互作用有关，NF-κ B活性被Bu 4 ManNAc选择性下调。总体而言，这些结果为SCFA-己糖胺杂合分子建立了一个新的治疗终点（侵袭控制），定义了参与细胞移动性的分子参与者的相对贡献，并证明Bu 4 ManNAc打破了有益HDACi活性与同时有害的NF-κB活化之间的混淆联系，这通常在表观遗传药物候选物中发现。
Per-butanoylated N-acetyl-d-mannosamine (Bu4ManNAc), a SCFA-hexosamine cancer drug candidate with activity manifest through intact n-butyrate-carbohydrate linkages, reduced the invasion of metastatic MDA-MB-231 breast cancer cells unlike per-butanoylated-d-mannose (Bu5Man), a clinically-tested compound that did not alter cell mobility. To gain molecular-level insight, therapeutic targets implicated in metastasis were investigated. The active compound Bu4ManNAc reduced both MUC1 expression and MMP-9 activity (via down-regulation of CXCR4 transcription) whereas ‘inactive’ Bu5Man had counterbalancing effects on these oncogenes. This divergent impact on transcription was linked to interplay between HDACi activity (held by both Bu4ManNAc and Bu5Man) and NF-κB activity, which was selectively down-regulated by Bu4ManNAc. Overall, these results establish a new therapeutic endpoint (control of invasion) for SCFA-hexosamine hybrid molecules, define relative contributions of molecular players involved in cell mobility, and demonstrate that Bu4ManNAc breaks the confounding link between beneficial HDACi activity and the simultaneous deleterious activation of NF-κB often found in epigenetic drug candidates.
登录
查看更多内容
影响因子：
24.5
作者：
FINNIE, IA;DWARAKANATH, AD;RHODES, JM
通讯作者：
RHODES, JM
影响因子：
2.9
作者：
Kim, EJ;Jones, MB;Yarema, KJ
通讯作者：
Yarema, KJ
影响因子：
64.8
作者：
Finnin, MS;Donigian, JR;Pavletich, NP
通讯作者：
Pavletich, NP
影响因子：
56.9
作者：
Mahal, LK;Yarema, KJ;Bertozzi, CR
通讯作者：
Bertozzi, CR
影响因子：
3.2
作者：
Basson, MD;Liu, YW;Rothberg, BEG
通讯作者：
Rothberg, BEG