PDF(Pubmed)
Abstract：
Prostate cancer (PCa) poses significant challenges in treatment, particularly when it progresses to a metastatic, castrate-resistant state. Conventional therapies, including chemotherapy, radiotherapy, and hormonal treatments, often fail due to toxicities, off-target effects, and acquired resistance. This research perspective defines an alternative therapeutic strategy focusing on the metabolic vulnerabilities of PCa cells, specifically their reliance on non-essential amino acids such as cysteine. Using an engineered enzyme cyst(e)inase to deplete the cysteine/cystine can induce oxidative stress and DNA damage in cancer cells. This depletion elevates reactive oxygen species (ROS) levels, disrupts glutathione synthesis, and enhances DNA damage, leading to cancer cell death. The combinatorial use of cyst(e)inase with agents targeting antioxidant defenses, such as thioredoxins, further amplifies ROS accumulation and cytotoxicity in PCa cells. Overall, in this perspective provides a compressive overview of the previous work on manipulating amino acid metabolism and redox balance modulate the efficacy of DNA repair-targeted and immune checkpoint blockade therapies in prostate cancer.
摘要：
前列腺癌（PCa）在治疗中提出了重大挑战，特别是当它进展到转移性时，去势抵抗状态。常规疗法,包括化疗,放射治疗,和荷尔蒙治疗，经常由于毒性而失败，脱靶效应,和获得的抵抗力。本研究视角定义了一种替代治疗策略，专注于PCa细胞的代谢脆弱性，特别是它们对非必需氨基酸如半胱氨酸的依赖。使用工程化的酶囊肿（e）酶来消耗半胱氨酸/胱氨酸可以诱导癌细胞中的氧化应激和DNA损伤。这种消耗提高了活性氧（ROS）的水平，破坏谷胱甘肽的合成，增强DNA损伤,导致癌细胞死亡.囊肿（e）酶与靶向抗氧化剂防御的药物的组合使用，如硫氧还蛋白，进一步放大PCa细胞中的ROS积累和细胞毒性。总的来说,在这一观点中,我们对先前关于操纵氨基酸代谢和氧化还原平衡调节前列腺癌中DNA修复靶向和免疫检查点阻断疗法的功效的工作进行了全面概述.
