Re-programming tumour cell metabolism to treat cancer: no lone target for lonidamine.
Re-programming tumour cell metabolism to treat cancer: no lone target for lonidamine.
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DOI：
10.1042/bcj20160068
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发表时间：
2016-06-01
期刊：
影响因子：
--
通讯作者：
Ganapathy V
中科院分区：
文献类型：
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作者：
Bhutia YD;Babu E;Ganapathy V
肿瘤细胞代谢与正常细胞代谢非常不同;癌细胞以优化其增殖、生长和存活的方式重新编程正常细胞中发生的代谢途径。虽然这种代谢重新编程显然对肿瘤有利，但它也为有效的癌症治疗提供了独特的机会。靶向肿瘤细胞特异性代谢途径的分子具有作为新型抗癌药物的潜力。氯尼达明属于这类分子，已经在一些国家用于癌症治疗。长期以来，人们已经知道氯尼达明通过抑制己糖激酶II（HKII）（一种糖酵解酶）来干扰肿瘤细胞中的能量产生。然而，随后的研究发现了该药物的其他药理学靶点，包括电子传递链和线粒体渗透性转换孔，从而扩大了该药物对肿瘤细胞代谢的药理学作用。Nancolas等人在最近一期《生物化学杂志》上的一项研究确定了氯尼达明的另外两个新靶点：线粒体中的丙酮酸转运蛋白和质膜（PM）中的H+偶联单羧酸转运蛋白。因此，越来越明显的是，氯尼达明的抗癌作用不是通过单一靶点发生的;该药物在多个部位起作用。无论分子靶点如何，氯尼达明最终所做的是撤销肿瘤细胞在重新编程细胞代谢和线粒体功能方面所做的事情。
Tumour cell metabolism is very different from normal cell metabolism; cancer cells re-programme the metabolic pathways that occur in normal cells in such a manner that it optimizes their proliferation, growth and survival. Although this metabolic re-programming obviously operates to the advantage of the tumour, it also offers unique opportunities for effective cancer therapy. Molecules that target the tumour cell-specific metabolic pathways have potential as novel anti-cancer drugs. Lonidamine belongs to this group of molecules and is already in use in some countries for cancer treatment. It has been known for a long time that lonidamine interferes with energy production in tumour cells by inhibiting hexokinase II (HKII), a glycolytic enzyme. However, subsequent studies have uncovered additional pharmacological targets for the drug, which include the electron transport chain and the mitochondrial permeability transition pore, thus expanding the pharmacological effects of the drug on tumour cell metabolism. A study by Nancolas et al. in a recent issue of the Biochemical Journal identifies two additional new targets for lonidamine: the pyruvate transporter in the mitochondria and the H+-coupled monocarboxylate transporters in the plasma membrane (PM). It is thus becoming increasingly apparent that the anti-cancer effects of lonidamine do not occur through a single target; the drug works at multiple sites. Irrespective of the molecular targets, what lonidamine does in the end is to undo what the tumour cells have done in terms of re-programming cellular metabolism and mitochondrial function.