Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate.
Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate.
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DOI：
10.1038/onc.2011.113
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发表时间：
2011-09-22
期刊：
影响因子：
8
通讯作者：
Thangaraju, M.
中科院分区：
文献类型：
--
作者：
Babu, E.;Ramachandran, S.;CoothanKandaswamy, V.;Elangovan, S.;Prasad, P. D.;Ganapathy, V.;Thangaraju, M.
关键词：
公众和科学家对二氯乙酸作为潜在抗癌药物的兴趣日益浓厚。存在可靠的证据证明该化合物具有抗肿瘤活性，但需要高浓度才能产生显着的治疗效果。不幸的是，这些高浓度会产生涉及神经系统的有害副作用，从而妨碍其用于癌症治疗。该化合物抗肿瘤活性的机制基础是其通过抑制丙酮酸脱氢酶激酶来激活丙酮酸脱氢酶复合物的能力。由于该化合物在微摩尔浓度下抑制激酶，因此尚不清楚为什么需要治疗上禁止的高剂量来抑制肿瘤生长。我们假设二氯乙酸缺乏进入肿瘤细胞的有效机制可能是造成这种现象的原因。在这里，我们证明 SLC5A8 以高亲和力非常有效地转运二氯乙酸。这种转运蛋白在正常细胞中表达，但在肿瘤细胞中通过表观遗传机制表达被沉默。转运蛋白的缺乏使得肿瘤细胞对二氯乙酸的抗肿瘤活性产生抵抗。然而，如果转运蛋白在肿瘤细胞中异位表达，则细胞对低浓度的药物变得敏感。这在乳腺癌细胞、结肠癌细胞和前列腺癌细胞中很明显。然而，组成型表达转运蛋白的正常细胞不受该化合物的影响，表明肿瘤细胞选择性治疗活性。该化合物的抗肿瘤活性机制仍然是其抑制丙酮酸脱氢酶激酶并迫使线粒体氧化丙酮酸的能力。由于肿瘤中 SLC5A8 的沉默涉及 DNA 甲基化，并且可以通过 DNA 甲基化抑制剂治疗来诱导其表达，因此我们的研究结果表明，将二氯乙酸盐与 DNA 甲基化抑制剂联合使用将提供一种减少二氯乙酸盐剂量的方法，以避免与高剂量相关的有害影响，但又不影响抗肿瘤活性。
There has been growing interest among the public and scientists in dichloroacetate as a potential anticancer drug. Credible evidence exists for the antitumor activity of this compound, but high concentrations are needed for significant therapeutic effect. Unfortunately, these high concentrations produce detrimental side effects involving nervous system, thereby precluding its use for cancer treatment. The mechanistic basis of the compound’s antitumor activity is its ability to activate pyruvate dehydrogenase complex through inhibition of pyruvate dehydrogenase kinase. Since the compound inhibits the kinase at micromolar concentrations, it is not known why therapeutically prohibitive high doses are needed for suppression of tumor growth. We hypothesized that lack of effective mechanisms for the entry of dichloroacetate into tumor cells may underlie this phenomenon. Here we show that SLC5A8 transports dichloroacetate very effectively with high affinity. This transporter is expressed in normal cells, but the expression is silenced in tumor cells via epigenetic mechanisms. The lack of the transporter makes tumor cells resistant to the antitumor activity of dichloroacetate. However, if the transporter is expressed in tumor cells ectopically, the cells become sensitive to the drug at low concentrations. This is evident in breast cancer cells, colon cancer cells, and prostate cancer cells. Normal cells, which constitutively express the transporter, are however not affected by the compound, indicating the tumor cell-selective therapeutic activity. The mechanism of the antitumor activity of the compound is still its ability to inhibit pyruvate dehydrogenase kinase and force mitochondrial oxidation of pyruvate. Since the silencing of SLC5A8 in tumors involves DNA methylation and its expression can be induced by treatment with DNA methylation inhibitors, our findings suggest that combining dichloroacetate with a DNA methylation inhibitor would offer a means to reduce the doses of dichloroacetate to avoid detrimental effects associated with high doses but without compromising antitumor activity.
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DOI：
10.1097/nen.0b013e3181b40217
发表时间：
2009-09
影响因子：
3.2
作者：
Calcutt NA;Lopez VL;Bautista AD;Mizisin LM;Torres BR;Shroads AL;Mizisin AP;Stacpoole PW
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影响因子：
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作者：
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