Morinaga Sei, Mizuta Kohei, Kang Byung Mo, Han Qinghong, Bouvet Michael, Yamamoto Norio, Hayashi Katsuhiro, Kimura Hiroaki, Miwa Shinji, Igarashi Kentaro, Higuchi Takashi, Tsuchiya Hiroyuki, Demura Satoru, Hoffman Robert M
AntiCancer Inc., San Diego, CA, U.S.A.
Department of Surgery, University of California, San Diego, CA, U.S.A.
In Vivo. 2025 May-Jun;39(3):1275-1282. doi: 10.21873/invivo.13931.
BACKGROUND/AIM: Eribulin is a microtubule inhibitor used in the treatment of various malignancies, including soft-tissue sarcoma. However, the development of eribulin resistance is a recalcitrant clinical problem. The present study demonstrates that super eribulin-resistant HT1080 human fibrosarcoma cells become highly malignant but can be eradicated synergistically by the combination of eribulin and methionine restriction in nude mice.
The cell viability of parental HT1080 cells and super eribulin-resistant HT1080 was determined following eribulin treatment using the WST-8 reagent. invasion assays, comprising wound-healing of cell monolayers, were performed to determine the degree of malignancy. Tumor growth to determine malignancy and tumor-growth sensitivity to eribulin, or a methionine-restricted diet, or their combination were analyzed in athymic nude mice.
The IC of eribulin for parental HT1080 cells was 0.15 nM, whereas for super eribulin-resistant HT1080 cells, the IC of eribulin was 18 nM, a 120-fold increase. Super eribulin-resistant HT1080 cells had a more rapid wound-healing closure rate than their parental HT1080 cells, indicating increased malignancy. Similarly, , untreated super eribulin-resistant HT1080 tumors grew faster than parental HT1080 tumors, confirming their high malignancy. The combination of a methionine-restricted diet and eribulin synergistically arrested super eribulin-resistant HT1080 tumors. Methionine restriction sensitized these highly resistant and malignant cells to eribulin.
Methionine restriction combined with eribulin represents a promising strategy to effectively treat eribulin-resistant high-malignancy fibrosarcoma, that can be immediately applied to the clinic.
背景/目的：艾瑞布林是一种微管抑制剂，用于治疗包括软组织肉瘤在内的多种恶性肿瘤。然而，艾瑞布林耐药性的产生是一个棘手的临床问题。本研究表明，对艾瑞布林具有超强耐药性的HT1080人纤维肉瘤细胞具有高度恶性，但在裸鼠中，艾瑞布林与蛋氨酸限制联合使用可协同根除这些细胞。
使用WST-8试剂测定经艾瑞布林处理后亲本HT1080细胞和对艾瑞布林具有超强耐药性的HT1080细胞的细胞活力。进行侵袭试验，包括细胞单层的伤口愈合试验，以确定恶性程度。在无胸腺裸鼠中分析肿瘤生长情况，以确定恶性程度以及肿瘤对艾瑞布林、蛋氨酸限制饮食或二者联合的生长敏感性。
艾瑞布林对亲本HT1080细胞的半数抑制浓度（IC）为0.15 nM，而对艾瑞布林具有超强耐药性的HT1080细胞，艾瑞布林的IC为18 nM，增加了120倍。对艾瑞布林具有超强耐药性的HT1080细胞的伤口愈合闭合速度比其亲本HT1080细胞更快，表明恶性程度增加。同样，未经处理的对艾瑞布林具有超强耐药性的HT1080肿瘤比亲本HT1080肿瘤生长更快，证实了它们的高恶性程度。蛋氨酸限制饮食与艾瑞布林联合可协同抑制对艾瑞布林具有超强耐药性的HT1080肿瘤。蛋氨酸限制使这些高度耐药且恶性的细胞对艾瑞布林敏感。
蛋氨酸限制与艾瑞布林联合是一种有前景的策略，可有效治疗对艾瑞布林耐药的高恶性纤维肉瘤，且可立即应用于临床。
