Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University of Chicago Medical Center, Maywood, IL 60153, USA.
Biochem Biophys Res Commun. 2010 May 28;396(2):495-500. doi: 10.1016/j.bbrc.2010.04.126. Epub 2010 Apr 27.
Clinicians successfully utilize high uptake of radiolabeled glucose via PET scanning to localize metastases in melanoma patients. To take advantage of this altered metabolome, 3-bromopyruvate (BrPA) was used to overcome the notorious resistance of melanoma to cell death. Using four melanoma cell lines, BrPA triggered caspase independent necrosis in two lines, whilst the other two lines were resistant to killing. Mechanistically, sensitive cells differed from resistant cells by; constitutively lower levels of glutathione, reduction of glutathione by BrPA only in sensitive cells; increased superoxide anion reactive oxygen species, loss of outer mitochondrial membrane permeability, and rapid ATP depletion. Sensitive cell killing was blocked by N-acetylcysteine or glutathione. When glutathione levels were reduced in resistant cell lines, they became sensitive to killing by BrPA. Taken together, these results identify a metabolic-based Achilles' heel in melanoma cells to be exploited by use of BrPA. Future pre-clinical and clinical trials are warranted to translate these results into improved patient care for individuals suffering from metastatic melanoma.
临床医生成功地利用 PET 扫描中放射性标记葡萄糖的高摄取率来定位黑色素瘤患者的转移灶。为了利用这种改变的代谢组，3-溴丙酮酸（BrPA）被用于克服黑色素瘤对细胞死亡的明显抵抗。使用四种黑色素瘤细胞系，BrPA 在两种细胞系中引发了半胱天冬酶非依赖性坏死，而另外两种细胞系则对杀伤有抵抗力。从机制上讲，敏感细胞与耐药细胞的区别在于：谷胱甘肽水平始终较低，BrPA 仅在敏感细胞中降低谷胱甘肽水平；超氧阴离子活性氧增加，线粒体膜通透性丧失，以及迅速耗尽 ATP。N-乙酰半胱氨酸或谷胱甘肽可阻断敏感细胞的杀伤。当耐药细胞系中的谷胱甘肽水平降低时，它们对 BrPA 的杀伤变得敏感。总之，这些结果确定了黑色素瘤细胞中基于代谢的致命弱点，可以利用 BrPA 加以利用。未来的临床前和临床试验是必要的，将这些结果转化为改善患有转移性黑色素瘤的个体的患者护理。
