Lactate dehydrogenase-A inhibition induces human glioblastoma multiforme stem cell differentiation and death.
Lactate dehydrogenase-A inhibition induces human glioblastoma multiforme stem cell differentiation and death.
复制标题
DOI：
10.1038/srep15556
复制
发表时间：
2015-10-23
影响因子：
4.6
通讯作者：
Martini C
中科院分区：
文献类型：
--
作者：
Daniele S;Giacomelli C;Zappelli E;Granchi C;Trincavelli ML;Minutolo F;Martini C
靶向肿瘤干细胞（CSCs）信号转导和代谢途径的治疗是有效降低多形性胶质母细胞瘤（GBM）复发并显著改善预后的创新策略。CSC表现出增加的糖酵解速率，从而使它们本质上对基于抑制糖酵解途径的前瞻性治疗策略更敏感。催化丙酮酸和乳酸相互转化的酶乳酸脱氢酶-A（LDH-A）在人类癌症（包括GBM）中上调。尽管有几篇论文已经探索了靶向GBM中癌症代谢的益处，但尚未研究直接LDH-A抑制在神经胶质肿瘤中的作用，特别是在干细胞亚群中。在此，在GBM衍生的CSC中研究了两种代表性LDH-A抑制剂（NHI-1和NHI-2），并与分化的肿瘤细胞进行了比较。LDH-A抑制在从不同GBM细胞系分离的CSC中特别有效，其中两种化合物阻断CSC形成并通过触发细胞凋亡和细胞分化引起持久作用。这些数据表明GBM，特别是干细胞亚群，对糖酵解抑制敏感，并揭示了LDH-A抑制剂在这种肿瘤类型中的治疗潜力。
Therapies that target the signal transduction and metabolic pathways of cancer stem cells (CSCs) are innovative strategies to effectively reduce the recurrence and significantly improve the outcome of glioblastoma multiforme (GBM). CSCs exhibit an increased rate of glycolysis, thus rendering them intrinsically more sensitive to prospective therapeutic strategies based on the inhibition of the glycolytic pathway. The enzyme lactate dehydrogenase-A (LDH-A), which catalyses the interconversion of pyruvate and lactate, is up-regulated in human cancers, including GBM. Although several papers have explored the benefits of targeting cancer metabolism in GBM, the effects of direct LDH-A inhibition in glial tumours have not yet been investigated, particularly in the stem cell subpopulation. Here, two representative LDH-A inhibitors (NHI-1 and NHI-2) were studied in GBM-derived CSCs and compared to differentiated tumour cells. LDH-A inhibition was particularly effective in CSCs isolated from different GBM cell lines, where the two compounds blocked CSC formation and elicited long-lasting effects by triggering both apoptosis and cellular differentiation. These data demonstrate that GBM, particularly the stem cell subpopulation, is sensitive to glycolytic inhibition and shed light on the therapeutic potential of LDH-A inhibitors in this tumour type.