From delocalized lipophilic cations to hypoxia: blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors.
From delocalized lipophilic cations to hypoxia: blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors.
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DOI：
10.1002/mnfr.200700457
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发表时间：
2009-01
影响因子：
5.2
通讯作者：
Lampidis, Theodore J.
中科院分区：
文献类型：
--
作者：
Kurtoglu, Metin;Lampidis, Theodore J.
癌症细胞和心肌细胞对蒽环类药物和离域亲脂性阳离子 (DLC) 的敏感性出人意料地相似，这引发了一系列研究，这些研究表明这些化合物的正电荷对于它们在这两种不同细胞类型中的选择性积累和毒性至关重要。解释这一现象的初步发现是，癌症和心肌细胞表现出高负质膜电位，导致这些药物的摄取增加。然而，p-糖蛋白外排泵被证明是这些化合物差异积累的另一个因素，因为它识别带正电荷的药物，从而主动降低其细胞内浓度。 DLC 的离域正电荷和亲脂性导致它们在线粒体中保留并抑制 ATP 合成。多年后，人们意识到实体瘤缺氧部分的癌细胞与 DLC 治疗的癌细胞相似，主要依靠无氧代谢生存，因此可以用糖酵解抑制剂 2-脱氧-d-葡萄糖 (2-DG) 来靶向。这一假设引发了一项 I 期临床试验，其中 2-DG 用于选择性杀死对标准化疗或放疗有抵抗力的缺氧肿瘤细胞群。
An unexpected similarity between cancer and cardiac muscle cells in their sensitivity to anthracyclines and delocalized lipophilic cations (DLC) prompted a series of studies in which it was shown that the positive charge of these compounds is central to their selective accumulation and toxicity in these two distinct cell types. An initial finding to explain this phenomenon was that cancer and cardiac muscle cells exhibit high negative plasma membrane potentials resulting in increased uptake of these agents. However, the p-glycoprotein efflux pump was shown to be another factor underlying differential accumulation of these compounds, since it recognizes positively charged drugs and thereby actively reduces their intracellular concentrations. The delocalized positive charge and lipophilicity of DLCs leads to their retention and inhibition of ATP synthesis in mitochondria. Years later it was realized that cancer cells in the hypoxic portions of solid tumors were similar to those treated with DLCs in relying mainly on anaerobic metabolism for survival and could thus be targeted with a glycolytic inhibitor, 2-deoxy-d-glucose (2-DG). This hypothesis has lead to a Phase I clinical trial in which 2-DG is used to selectively kill the hypoxic tumor cell population which are resistant to standard chemotherapy or radiation.
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DOI：
10.1101/sqb.1982.046.01.018
发表时间：
1981-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
CHEN, LB;SUMMERHAYES, IC;LAMPIDIS, TJ
通讯作者：
LAMPIDIS, TJ
影响因子：
64.5
作者：
JOHNSON, LV;SUMMERHAYES, IC;CHEN, LB
通讯作者：
CHEN, LB
影响因子：
4.4
作者：
Boutrid, Hinda;Jockovich, Maria-Elena;Cebulla, Colleen M.
通讯作者：
Cebulla, Colleen M.
影响因子：
11.4
作者：
Edgar, R;Bibi, E
通讯作者：
Bibi, E
DOI：
10.1073/pnas.77.2.990
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
JOHNSON, LV;WALSH, ML;CHEN, LB
通讯作者：
CHEN, LB