Recombinant Methioninase Increases Eribulin Efficacy 16-fold in Highly Eribulin-resistant HT1080 Fibrosarcoma Cells, Demonstrating Potential to Overcome the Clinical Challenge of Drug-resistant Soft-tissue Sarcoma.

IF 1.6 4区医学 Q4 ONCOLOGY

Anticancer research Pub Date : 2024-09-01 DOI:10.21873/anticanres.17202

Sei Morinaga, Qinghong Han, Kohei Mizuta, Byung Mo Kang, Motokazu Sato, Michael Bouvet, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Kentaro Igarashi, Takashi Higuchi, Hiroyuki Tsuchiya, Satoru Demura, Robert M Hoffman

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Abstract

Background/aim: A major challenge in treating soft-tissue sarcoma is the development of drug resistance. Eribulin, an anti-tubulin agent, is used as a second-line chemotherapy for patients with unresectable or metastatic soft-tissue sarcoma. However, most patients with advanced soft-tissue sarcoma are resistant to eribulin and do not survive. Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect. The present study aimed to show how much rMETase could increase the efficacy of eribulin on eribulin-resistant fibrosarcoma cells in vitro.

Materials and methods: HT1080 human fibrosarcoma cells were exposed to step-wise increasing concentrations of eribulin from 0.15-0.4 nM to establish eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were cultured in vitro and divided into four groups: untreated control; eribulin treated (0.15 nM); rMETase treated (0.75 U/ml); and eribulin (0.15 nM) plus rMETase (0.75 U/ml) treated.

Results: The IC₅₀ of eribulin on ER-HT1080 cells was 0.95 nM compared to the IC₅₀ of 0.15 nM on HT1080 cells, a 6-fold increase. The IC₅₀ of rMETase on ER-HT1080 and HT1080 was 0.87 U/ml and 0.75 U/ml, respectively. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in an inhibition of 80.1% compared to eribulin alone (5.0%) or rMETase alone (47.1%) (p<0.05). rMETase thus increased the efficacy of eribulin 16-fold on eribulin-resistant fibrosarcoma cells.

Conclusion: The present study showed that the combination of eribulin and rMETase can overcome high eribulin resistance of fibrosarcoma. The present results demonstrate that combining rMETase with first- or second-line therapy for soft-tissue sarcoma has the potential to overcome the intractable clinical problem of drug-resistant soft-tissue sarcoma.

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重组甲硫氨酸酶使高度耐药的 HT1080 纤维肉瘤细胞的 Eribulin 疗效提高了 16 倍，显示了克服耐药软组织肉瘤临床挑战的潜力。

背景/目的：治疗软组织肉瘤的一大挑战是耐药性的产生。艾瑞布林是一种抗微管蛋白药物，被用作不可切除或转移性软组织肉瘤患者的二线化疗药物。然而，大多数晚期软组织肉瘤患者对艾瑞布林产生耐药性，无法存活。重组蛋氨酸酶（rMETase）针对的是癌症的基本和普遍特征--蛋氨酸成瘾，即霍夫曼效应。材料与方法：将 HT1080 人纤维肉瘤细胞暴露于浓度从 0.15-0.4 nM 逐步增加的麦角新碱中，以建立麦角新碱耐药 HT1080（ER-HT1080）。ER-HT1080细胞经体外培养后分为四组：未处理对照组；埃里布林处理组（0.15 nM）；rMET酶处理组（0.75 U/ml）；埃里布林（0.15 nM）加rMET酶（0.75 U/ml）处理组：结果：艾瑞布林对ER-HT1080细胞的IC50为0.95 nM，而对HT1080细胞的IC50为0.15 nM，增加了6倍。rMETase 对 ER-HT1080 和 HT1080 细胞的 IC50 分别为 0.87 U/ml 和 0.75 U/ml 。rMET酶（0.75 U/ml）和艾瑞布林（0.15 nM）的组合对ER-HT1080细胞有协同作用，与艾瑞布林单独作用（5.0%）或rMET酶单独作用（47.1%）相比，抑制率达80.1%（P结论：本研究表明，艾瑞布林和rMET酶联合使用可克服纤维肉瘤对艾瑞布林的高耐药性。本研究结果表明，将 rMETase 与软组织肉瘤的一线或二线疗法相结合，有望克服软组织肉瘤耐药这一棘手的临床问题。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Anticancer research 医学-肿瘤学

CiteScore

3.70

自引率

10.00%

发文量

566

审稿时长

2 months

期刊介绍： ANTICANCER RESEARCH is an independent international peer-reviewed journal devoted to the rapid publication of high quality original articles and reviews on all aspects of experimental and clinical oncology. Prompt evaluation of all submitted articles in confidence and rapid publication within 1-2 months of acceptance are guaranteed. ANTICANCER RESEARCH was established in 1981 and is published monthly (bimonthly until the end of 2008). Each annual volume contains twelve issues and index. Each issue may be divided into three parts (A: Reviews, B: Experimental studies, and C: Clinical and Epidemiological studies). Special issues, presenting the proceedings of meetings or groups of papers on topics of significant progress, will also be included in each volume. There is no limitation to the number of pages per issue.