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3-溴丙酮酸作为一种有效的抗癌疗法,以纪念已故的安德烈·戈菲教授。

3-Bromopyruvate as a potent anticancer therapy in honor and memory of the late Professor André Goffeau.

作者信息

Ko Young H, Niedźwiecka Katarzyna, Casal Margarida, Pedersen Peter L, Ułaszewski Stanisław

机构信息

KoDiscovery, LLC, University of Maryland BioPark, Baltimore, Maryland, USA.

Institute of Genetics and Microbiology, University of Wrocław, Wrocław, Poland.

出版信息

Yeast. 2019 Apr;36(4):211-221. doi: 10.1002/yea.3367. Epub 2018 Dec 13.

Abstract

3-Bromopyruvate (3BP) is a small, highly reactive molecule formed by bromination of pyruvate. In the year 2000, the antitumor properties of 3BP were discovered. Studies using animal models proved its high efficacy for anticancer therapy with no apparent side effects. This was also found to be the case in a limited number of cancer patients treated with 3BP. Due to the "Warburg effect," most tumor cells exhibit metabolic changes, for example, increased glucose consumption and lactic acid production resulting from mitochondrial-bound overexpressed hexokinase 2. Such alterations promote cell migration, immortality via inhibition of apoptosis, and less dependence on the availability of oxygen. Significantly, these attributes also make cancer cells more sensitive to agents, such as 3BP that inhibits energy production pathways without harming normal cells. This selectivity of 3BP is mainly due to overexpressed monocarboxylate transporters in cancer cells. Furthermore, 3BP is not a substrate for any pumps belonging to the ATP-binding cassette superfamily, which confers resistance to a variety of drugs. Also, 3BP has the capacity to induce multiple forms of cell death, by, for example, ATP depletion resulting from inactivation of both glycolytic and mitochondrial energy production pathways. In addition to its anticancer property, 3BP also exhibits antimicrobial activity. Various species of microorganisms are characterized by different susceptibility to 3BP inhibition. Among tested strains, the most sensitive was found to be the pathogenic yeast-like fungus Cryptococcus neoformans. Significantly, studies carried out in our laboratories have shown that 3BP exhibits a remarkable capacity to eradicate cancer cells, fungi, and algae.

摘要

3-溴丙酮酸(3BP)是一种通过丙酮酸溴化形成的小分子、高反应性分子。2000年,人们发现了3BP的抗肿瘤特性。使用动物模型的研究证明其在抗癌治疗中疗效显著且无明显副作用。在少数接受3BP治疗的癌症患者中也发现了同样的情况。由于“瓦伯格效应”,大多数肿瘤细胞会出现代谢变化,例如,由于线粒体结合的己糖激酶2过表达导致葡萄糖消耗增加和乳酸生成增多。这些改变促进细胞迁移、通过抑制凋亡实现永生以及减少对氧气供应的依赖。值得注意的是,这些特性也使癌细胞对3BP等抑制能量产生途径而不损害正常细胞的药物更加敏感。3BP的这种选择性主要归因于癌细胞中过表达的单羧酸转运体。此外,3BP不是ATP结合盒超家族中任何一种泵的底物,这赋予了它对多种药物的抗性。而且,3BP有能力诱导多种形式的细胞死亡,例如,通过糖酵解和线粒体能量产生途径失活导致ATP耗竭。除了其抗癌特性外,3BP还具有抗菌活性。各种微生物对3BP抑制的敏感性不同。在测试菌株中,发现最敏感的是致病性酵母样真菌新型隐球菌。值得注意的是,我们实验室进行的研究表明,3BP具有显著的根除癌细胞、真菌和藻类的能力。

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