肿瘤病人要同时限糖限肉-谷氨酰胺（Glutamine）促进肿瘤的生长

　

　

肉类含有大量的蛋白质。谷氨酰胺是肌肉中最丰富的游离氨基酸，它占人体游离氨基酸总量的60％，也就是三分之二。

任何富含蛋白质的食物都富含谷氨酰胺。肉被认为是谷氨酰胺最丰富的来源之一。牛肉、鸡肉和羊肉，海鲜，黄豆等种子都含很高的谷氨酰胺。

　

这个研究发现耐药癌细胞在化疗后，摄入二倍的谷氨酰胺，维持其生长和增殖。再次展示癌细胞顽强的生命力和超级聪明。癌症患者有必要坚持由遗传和生物学家Seyfried 倡导的生酮饮食（KETOGENIC DIET）- 同时控制糖和蛋白质尤其是富含谷氨酸的肉类的摄取。 

顺铂耐药仍然是肺癌治疗中的一个主要问题。我们已经发现，顺铂耐药(CR)肺癌细胞，无论信号通路的状态如何，都有共同的参数，即活性氧(ROS)的增加，并进行代谢重编程。

　

 

CR细胞不再依赖于糖酵解途径，而是依赖于氧化代谢。他们摄入了两倍的谷氨酰胺 （Glutamine)，对谷氨酰胺的缺乏非常敏感。谷氨酰胺被水解成谷氨酸用于谷胱甘肽的合成，这是通过xCT逆转运蛋白消除高ROS的一个重要因素。因此，用riluzole(一种被批准的药物)阻断谷氨酸流量，可以在体外和体内选择性地杀死CR细胞。

　

 

然而，我们在这里发现，谷胱甘肽抑制并不是根除CR细胞的主要途径。Riluzole可导致NAD+(烟酰胺腺嘌呤二核苷酸)和乳酸脱氢酶(LDHA)的进一步降低，从而进一步加剧CR细胞的氧化应激。LDHA敲除细胞对Riluzole治疗具有高度敏感性，并具有较高的ROS水平。添加NAD+再稳定LDHA和逆转Riluzole诱导的细胞死亡。

 

到目前为止，还没有任何药物能够克服顺铂耐药或杀死顺铂耐药的细胞。CR细胞具有较高的ROS水平，并进行代谢重编程。这些代谢的适应性可以被Riluzole利用和靶向。Riluzole可作为双重靶向药物，抑制LDHA，阻断xCT抗转运蛋白。对于顺铂耐药肺癌患者的未来治疗，再次建议考虑使用Riluzole。

　

参考文献：

 

利用活性氧（ROS）和代谢差异杀死顺铂耐药的肺癌

Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer

 

Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter. Thus, blocking glutamate flux using riluzole (an amyotropic lateral sclerosis approved drug) can selectively kill CR cells in vitro and in vivo. However, we discovered here that glutathione suppression is not the primary pathway in eradicating the CR cells.

 

Riluzole can lead to further decrease in NAD+ (nicotinamide adenine dinucleotide) and lactate dehydrogenase-A (LDHA) expressions which in turn further heightened oxidative stress in CR cells. LDHA knocked-down cells became hypersensitive to riluzole treatments and possessed increased levels of ROS. Addition of NAD+ re-stabilized LDHA and reversed riluzole induced cell death. Thus far, no drugs are available which could overcome cisplatin resistance or kill cisplatin resistant cells. CR cells possess high levels of ROS and undergo metabolic reprogramming. These metabolic adaptations can be exploited and targeted by riluzole. Riluzole may serve as a dual-targeting agent by suppression LDHA and blocking xCT antiporter. Repurposing of riluzole should be considered for future treatment of cisplatin resistant lung cancer patients.

 

https://mdanderson.influuent.utsystem.edu/en/publications/exploiting-ros-and-metabolic-differences-to-kill-cisplatin-resist