Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES iScience Pub Date : 2025-01-17 DOI:10.1016/j.isci.2024.111525

Josephine Carpentier , Marta Freitas , Valle Morales , Katiuscia Bianchi , John Bomalaski , Peter Szlosarek , Sarah A. Martin

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Abstract

Pleural mesothelioma is a highly chemotherapy-resistant cancer. Approximately 50% of mesotheliomas do not express argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme in arginine biosynthesis, making arginine depletion with pegylated arginine deiminase (ADI-PEG20) an attractive therapeutic strategy. We investigated whether combinatory treatment composed of ADI-PEG20 and polyamine inhibitors constitutes a promising novel therapeutic strategy to overcome ADI-PEG20 resistance in mesothelioma patients. Treatment of ADI-PEG20-resistant cell lines with a range of different polyamine inhibitors demonstrated that ADI-PEG20-resistant cell lines were highly sensitive to the spermidine-analog GC7. We observed a synergistic effect of GC7 and ADI-PEG20 in both ADI-PEG20-sensitive and ADI-PEG20-resistant cell lines. Metabolomic analysis revealed that sensitivity to GC7 is due to inhibition of the Tricarboxylic (TCA) cycle. Significantly, combination of GC7 and ADI-PEG20 prevented the emergence of resistant cells in vitro. Taken together, we have identified the therapeutic potential of combinatorial treatment of ADI-PEG20 with GC7 for mesothelioma management.

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用GC7治疗胸膜间皮瘤克服精氨酸剥夺疗法的耐药性。

胸膜间皮瘤是一种高度耐化疗的癌症。大约50%的间皮瘤不表达精氨酸琥珀酸合成酶1 (ASS1)，这是精氨酸生物合成的限制性酶，因此用聚乙二醇化精氨酸脱亚胺酶（ADI-PEG20）来消耗精氨酸是一种有吸引力的治疗策略。我们研究了由ADI-PEG20和多胺抑制剂组成的联合治疗是否构成了克服间皮瘤患者ADI-PEG20耐药的有希望的新治疗策略。用一系列不同的多胺抑制剂处理adi - peg20耐药细胞系表明，adi - peg20耐药细胞系对亚精胺类似物GC7高度敏感。我们观察到GC7和ADI-PEG20在ADI-PEG20敏感和ADI-PEG20抗性细胞系中的协同作用。代谢组学分析显示，对GC7的敏感性是由于抑制三羧酸（TCA）循环。GC7与ADI-PEG20联合使用可显著抑制体外耐药细胞的产生。综上所述，我们已经确定了ADI-PEG20与GC7联合治疗间皮瘤的治疗潜力。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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