Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo
Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo
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DOI：
10.1007/s10549-009-0435-9
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发表时间：
2010-02-01
影响因子：
3.8
通讯作者：
Blackburn, Anneke C.
中科院分区：
文献类型：
--
作者：
Sun, Ramon C.;Fadia, Mitali;Blackburn, Anneke C.
糖酵解表型在包括乳腺癌在内的实体癌中是一种普遍的现象。二氯乙酸（DCA）最近被认为是一种新型且相对无毒的抗癌药物，可以通过抑制丙酮酸脱氢酶激酶来逆转癌细胞中的糖酵解表型。我们研究了DCA对乳腺癌细胞的作用，包括在一个高度转移的体内模型中。在体外实验中发现，DCA可以抑制几种乳腺癌细胞系的生长。对13762个MAT大鼠乳腺腺癌细胞的进一步检查发现，DCA对糖酵解表型的逆转与增殖抑制相关，而不增加细胞死亡。尽管caspase 3/7活性小幅但显著增加，这可能使癌细胞对其他凋亡触发因素敏感。在体内，将13762个MAT细胞注射到大鼠尾静脉后，DCA使宏观观察到的肺转移数量减少58% （P = 0.0001，每组千分之一）。这些结果表明，DCA除了具有促凋亡特性外，还具有抗增殖特性，并且在体内对高度转移性疾病有效，突出了其临床应用潜力。
The glycolytic phenotype is a widespread phenomenon in solid cancer forms, including breast cancer. Dichloroacetate (DCA) has recently been proposed as a novel and relatively non-toxic anti-cancer agent that can reverse the glycolytic phenotype in cancer cells through the inhibition of pyruvate dehydrogenase kinase. We have examined the effect of DCA against breast cancer cells, including in a highly metastatic in vivo model. The growth of several breast cancer cell lines was found to be inhibited by DCA in vitro. Further examination of 13762 MAT rat mammary adenocarcinoma cells found that reversal of the glycolytic phenotype by DCA correlated with the inhibition of proliferation without any increase in cell death. This was despite a small but significant increase in caspase 3/7 activity, which may sensitize cancer cells to other apoptotic triggers. In vivo, DCA caused a 58% reduction in the number of lung metastases observed macroscopically after injection of 13762 MAT cells into the tail vein of rats (P = 0.0001, n a parts per thousand yen 9 per group). These results demonstrate that DCA has anti-proliferative properties in addition to pro-apoptotic properties, and can be effective against highly metastatic disease in vivo, highlighting its potential for clinical use.