获得性吉西他滨耐药的c- myc表达升高的纤维肉瘤细胞对重组蛋氨酸酶仍然敏感:一种治疗顽固性疾病的潜在临床策略

Cancer diagnosis & prognosis Pub Date : 2025-01-03 eCollection Date: 2025-01-01 DOI:10.21873/cdp.10405
Sei Morinaga, Qinghong Han, Kohei Mizuta, Byung Mo Kang, 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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引用次数: 0

摘要

背景/目的:对于软组织肉瘤的二线化疗,吉西他滨与多西紫杉醇联合使用。然而,晚期软组织肉瘤的疗效有限,需要更有效的治疗方法。本研究的目的是比较rMETase和吉西他滨对HT1080人纤维肉瘤细胞和Hs27正常成纤维细胞的疗效,以及识别和有效治疗与c-MYC升高相关的吉西他滨耐药的HT1080细胞。患者和方法:采用WST-8试剂测定细胞活力。对HT1080和Hs27细胞进行了四组体外试验:吉西他滨单用、rMETase单用、吉西他滨加rMETase联用。通过在增加吉西他滨浓度(0.016 nM至16 nM)中培养HT-1080细胞5个月,建立了吉西他滨耐药细胞(GR-HT1080)。Western免疫印迹法检测HT1080和GR-HT1080细胞中c-MYC水平。结果:吉西他滨对HT1080细胞、GR-HT1080细胞和Hs27细胞的IC50分别为12.8 nM、30.8 nM和4.48 nM。HT1080的rMETase IC50值为0.75 U/ml。rMETase对GR-HT1080细胞的IC50值为0.85 U/ml。rMETase对Hs27细胞的IC50值为0.93 U/ml。吉西他滨和rMETase在杀死纤维肉瘤细胞方面显示出协同作用,但在正常成纤维细胞上没有观察到协同作用。与HT-1080细胞相比,GR-HT1080细胞的c-MYC水平高出5.1倍以上。亲代HT1080细胞和GR-HT1080细胞对rMETase具有相似的高敏感性。结论:rMETase可作为克服肉瘤吉西他滨耐药的临床策略。
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Elevated-c-MYC-expressing Fibrosarcoma Cells With Acquired Gemcitabine Resistance Remain Sensitive to Recombinant Methioninase: A Potential Clinical Strategy for a Recalcitrant Disease.

Background/aim: For second-line chemotherapy of soft-tissue sarcoma, gemcitabine is administered in combination with docetaxel. However, more effective treatments are required for advanced soft-tissue sarcoma, where the efficacy is limited. The purpose of the present study was to compare the efficacy of rMETase and gemcitabine against HT1080 human fibrosarcoma cells and Hs27 normal fibroblasts, as well as to identify and effectively treat HT1080 cells that are resistant to gemcitabine associated with elevated c-MYC.

Patients and methods: Cell viability was measured with the WST-8 reagent. Four groups of in vitro tests were conducted involving HT1080 and Hs27 cells: gemcitabine alone, rMETase alone, and a combination of gemcitabine plus rMETase. Gemcitabine resistant cells (GR-HT1080) were established by culturing HT-1080 cells in increasing concentrations of gemcitabine, ranging from 0.016 nM to 16 nM over five months. Western immunoblotting was performed to measure c-MYC levels in HT1080 and GR-HT1080 cells.

Results: Gemcitabine had an IC50 of 12.8 nM against HT1080 cells, 30.8 nM against GR-HT1080 cells, and 4.48 nM against Hs27 cells. The rMETase IC50 value for HT1080 was 0.75 U/ml. The IC50 value of rMETase for GR-HT1080 cells was 0.85 U/ml. The IC50 value for rMETase on Hs27 cells was 0.93 U/ml. Gemcitabine and rMETase demonstrated synergy in killing fibrosarcoma cells, but no synergy was observed on normal fibroblasts. The c-MYC level that was more than 5.1 times higher in GR-HT1080 cells compared to HT-1080 cells. Both the parental HT1080 cells and the GR-HT1080 cells had a similar high sensitivity to rMETase alone.

Conclusion: rMETase may be used as a future clinical strategy to overcome gemcitabine resistance in sarcoma.

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