Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.
Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.
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由于遗传变异和异常生长，癌细胞比非恶性细胞经历更高的活性氧（ROS）氧化应激，因此，维持抗氧化剂谷胱甘肽（GSH）对其生存和增殖至关重要。在升高的ROS条件下，内源性l-半胱氨酸（l-Cys）的产生不足以用于GSH合成，需要l-Cys摄取，主要是通过xCT（−）转运蛋白以其二硫化物形式l-胱氨酸（CSSC）摄取。在这里，我们表明，在小鼠和非人灵长类动物中，施用工程化的、酶优化的人Cyst（e）酶介导细胞外l-Cys和CSSC池的持续消耗，选择性地引起细胞周期停滞和死亡。（PI和膜联蛋白-V染色），这是由于细胞内GSH的耗尽和随后的ROS升高，但在小鼠中甚至在连续治疗数月后也没有明显的毒性。Cyst（e）inase抑制前列腺癌同种异体移植物的生长，减少前列腺癌和乳腺癌异种移植物中的肿瘤生长，并使发生类似人类慢性淋巴细胞白血病的TCL 1-Tg：p53−/−小鼠的中位生存时间增加一倍。酶介导的血清L-Cys和CSSC池的消耗抑制多种肿瘤的生长，但长时间耐受性良好的观察结果表明，Cyst（e）酶代表了一种安全有效的治疗方式，用于灭活广泛的恶性肿瘤中的抗氧化细胞应答。
Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than non-malignant cells due to genetic alterations and abnormal growth and as a result, maintenance of the anti-oxidant glutathione (GSH) is essential for their survival and proliferation. Under elevated ROS conditions endogenous l-Cysteine (l-Cys) production is insufficient for GSH synthesis, necessitating l-Cys uptake, predominantly in its disulfide form l-Cystine (CSSC) via the xCT(−) transporter. Here we show that administration of an engineered, pharmacologically optimized, human Cyst(e)inase enzyme mediates sustained depletion of the extracellular l-Cys and CSSC pool in mice and non-human primates, selectively causes cell cycle arrest and death (PI and Annexin-V staining) in cancer cells due to depletion of intracellular GSH and ensuing elevated ROS, yet results in no apparent toxicities in mice even after months of continuous treatment. Cyst(e)inase suppressed the growth of prostate carcinoma allografts, reduced tumor growth in prostate and breast cancer xenografts and doubled the median survival time of TCL1-Tg:p53−/− mice that develop disease resembling human chronic lymphocytic leukemia. The observation that enzyme-mediated depletion of the serum l-Cys and CSSC pool suppresses the growth of multiple tumors, yet is very well tolerated for prolonged periods suggests that Cyst(e)inase represents a safe and effective therapeutic modality for inactivating anti-oxidant cellular responses in a wide range of malignancies.
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