Exploiting metabolic vulnerabilities of cancer cells with nontoxic, plant derived compounds constitutes a novel strategy for both chemoprevention and treatment. A high-throughput screening approach was used to evaluate a library of natural products to determine the most synergistic combination in precursor-B cell acute lymphoblast leukemia. Dimethylaminoparthenolide and shikonin effectively inhibited proliferation resulting in cell death in primary and immortalized leukemia cells, while having negligible effects on normal cells. Dimethylaminoparthenolide and shikonin have been shown separately to inhibit cell survival and proliferative signaling and activate tumor suppressors and proapoptotic pathways. Untargeted metabolomics and metabolic flux analysis with stable isotopically labeled glucose and glutamine exhibited a global shift in metabolism following treatment. Pathway analysis indicated significant differences in amino acid, antioxidant, tricarboxylic acid cycle, and nucleotide metabolism. Together, dimethylaminoparthenolide and shikonin reduced the shunting of glycolytic intermediates into the pentose phosphate pathway for biosynthetic purposes. Similarly, the incorporation of glutamine and glutamine-derived metabolites into purine and pyrimidine synthesis was inhibited by the combination of dimethylaminoparthenolide and shikonin, effectively impeding biosynthetic pathways critical for leukemia cell survival. This approach demonstrates that a synergistic pair of compounds with malignant cell specificity can effectively target metabolic pathways crucial to leukemia cell proliferation and induce apoptosis.

中文翻译：

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二甲基氨基苯酚和紫草素的协同组合的鉴定改变了代谢并抑制了儿科前体-B细胞急性淋巴细胞白血病的增殖。

利用无毒的植物衍生化合物开发癌细胞的代谢脆弱性，是化学预防和治疗的新策略。高通量筛选方法用于评估天然产物库，以确定前体B细胞急性淋巴母细胞白血病中最协同的组合。二甲基氨基爬山虎和紫草素可有效抑制增殖，导致原代和永生化白血病细胞死亡，而对正常细胞的影响可忽略不计。已显示二甲基氨基单酚和紫草素分别抑制细胞存活和增殖信号传导并激活肿瘤抑制因子和促凋亡途径。用稳定的同位素标记的葡萄糖和谷氨酰胺进行的非靶向代谢组学和代谢通量分析显示出治疗后新陈代谢的整体变化。途径分析表明氨基酸，抗氧化剂，三羧酸循环和核苷酸代谢方面存在显着差异。出于生物合成的目的，二甲基氨基单酚和紫草素一起减少了糖酵解中间体进入戊糖磷酸途径的分流。同样，二甲基氨基单酚和紫草素的组合抑制了谷氨酰胺和谷氨酰胺衍生的代谢物向嘌呤和嘧啶的合成，有效地阻碍了对白血病细胞存活至关重要的生物合成途径。