Large regions in tumor tissues, particularly pancreatic cancer, are hypoxic and nutrient-deprived because of unregulated cell growth and insufficient vascular supply. Certain cancer cells, such as those inside a tumor, can tolerate these severe conditions and survive for prolonged periods. We hypothesized that small molecular agents, which can preferentially reduce cancer cell survival under nutrient-deprived conditions, could function as anticancer drugs. In this study, we constructed a high-throughput screening system to identify such small molecules and screened chemical libraries and microbial culture extracts. We were able to determine that some small molecular compounds, such as penicillic acid, papyracillic acid, and auranofin, exhibit preferential cytotoxicity to human pancreatic cancer cells under nutrient-deprived compared with nutrient-sufficient conditions. Further analysis revealed that these compounds target to redox systems such as GSH and thioredoxin and induce accumulation of reactive oxygen species in nutrient-deprived cancer cells, potentially contributing to apoptosis under nutrient-deprived conditions. Nutrient-deficient cancer cells are often deficient in GSH; thus, they are susceptible to redox system inhibitors. Targeting redox systems might be an attractive therapeutic strategy under nutrient-deprived conditions of the tumor microenvironment.

中文翻译：

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营养剥夺下的人类胰腺癌细胞容易受到氧化还原系统抑制。

由于细胞生长不受调节和血管供应不足，肿瘤组织中的大片区域（尤其是胰腺癌）处于缺氧和营养匮乏的状态。某些癌细胞，例如肿瘤内的癌细胞，可以耐受这些严酷的条件并长期存活。我们假设小分子药物可以在营养缺乏的条件下优先降低癌细胞的存活率，从而可以起到抗癌药物的作用。在本研究中，我们构建了一个高通量筛选系统来鉴定此类小分子，并筛选了化学文库和微生物培养提取物。我们能够确定一些小分子化合物，例如青霉酸、巴吡西林酸和金诺芬，与营养充足的条件相比，在营养缺乏的条件下对人胰腺癌细胞表现出优先的细胞毒性。进一步的分析表明，这些化合物以谷胱甘肽和硫氧还蛋白等氧化还原系统为目标，诱导营养缺乏的癌细胞中活性氧的积累，可能导致营养缺乏条件下的细胞凋亡。营养缺乏的癌细胞通常缺乏谷胱甘肽（GSH）；因此，它们容易受到氧化还原系统抑制剂的影响。在肿瘤微环境营养匮乏的条件下，靶向氧化还原系统可能是一种有吸引力的治疗策略。在营养缺乏的条件下可能导致细胞凋亡。营养缺乏的癌细胞通常缺乏谷胱甘肽（GSH）；因此，它们容易受到氧化还原系统抑制剂的影响。在肿瘤微环境营养匮乏的条件下，靶向氧化还原系统可能是一种有吸引力的治疗策略。在营养缺乏的条件下可能导致细胞凋亡。营养缺乏的癌细胞通常缺乏谷胱甘肽（GSH）；因此，它们容易受到氧化还原系统抑制剂的影响。在肿瘤微环境营养匮乏的条件下，靶向氧化还原系统可能是一种有吸引力的治疗策略。