文章：

子宫平滑肌肉瘤联合γ分泌酶抑制剂MK-0752与化疗药物治疗可降低细胞侵袭性并促进细胞凋亡

Combined Treatment of Uterine Leiomyosarcoma with Gamma Secretase Inhibitor MK-0752 and Chemotherapeutic Agents Decreases Cellular Invasion and Increases Apoptosis

原文发布日期：10 June 2024

DOI: 10.3390/cancers16122184

类型: Article

开放获取: 是

英文摘要：

Due to limited effective therapeutics for uterine leiomyosarcoma (uLMS), the impact of the gamma secretase inhibitor (GSI) MK-0752 with common chemotherapeutics was explored in uLMS. MTT assays were performed on two human uLMS cell lines, SK-UT-1B and SK-LMS-1, using MK-0752, docetaxel, doxorubicin, and gemcitabine, individually and in combination, to determine cell viability after treatment. Synergistic combinations were used in transwell invasion assays, cell cycle flow cytometry, proliferation assays, and RNA sequencing. In SK-UT-1B, MK-0752 was synergistic with doxorubicin and gemcitabine plus docetaxel. In SK-LMS-1, MK-0752 was synergistic with all individual agents and with the combination of gemcitabine plus docetaxel. MK-0752, gemcitabine, and docetaxel decreased invasion in SK-UT-1B 2.1-fold* and in SK-LMS-1 1.7-fold*. In SK-LMS-1, invasion decreased 1.2-fold* after treatment with MK-0752 and docetaxel and 2.2-fold* after treatment with MK-0752 and doxorubicin. Cell cycle analysis demonstrated increases in the apoptotic sub-G1 population with MK-0752 alone in SK-UT-1B (1.4-fold*) and SK-LMS-1 (2.7-fold**), along with increases with all combinations in both cell lines. The combination treatments had limited effects on proliferation, while MK-0752 alone decreased proliferation in SK-LMS-1 (0.63-fold**). Both MK-0752 alone and in combination altered gene expression and KEGG pathways. In conclusion, the combinations of MK-0752 with either doxorubicin, docetaxel, or gemcitabine plus docetaxel are potential novel therapeutic approaches for uLMS. (*p< 0.05, **p< 0.01).

摘要翻译： 

由于子宫平滑肌肉瘤（uLMS）的有效治疗方法有限，本研究探讨了γ-分泌酶抑制剂（GSI）MK-0752与常用化疗药物联合应用对uLMS的影响。采用MTT法检测两种人源uLMS细胞系（SK-UT-1B和SK-LMS-1）在单独或联合使用MK-0752、多西他赛、阿霉素和吉西他滨处理后的细胞活力。对具有协同作用的药物组合进一步进行Transwell侵袭实验、细胞周期流式检测、增殖实验及RNA测序分析。在SK-UT-1B细胞中，MK-0752与阿霉素及吉西他滨联合多西他赛方案均显示协同作用；在SK-LMS-1细胞中，MK-0752与所有单药及吉西他滨联合多西他赛方案均产生协同效应。MK-0752、吉西他滨与多西他赛三药联合使SK-UT-1B细胞侵袭能力降低2.1倍*，SK-LMS-1细胞降低1.7倍*。在SK-LMS-1细胞中，MK-0752联合多西他赛使侵袭能力下降1.2倍*，联合阿霉素则下降2.2倍*。细胞周期分析显示：单用MK-0752可使SK-UT-1B细胞凋亡亚G1期群体增加1.4倍*，SK-LMS-1细胞增加2.7倍**；所有联合用药方案在两种细胞系中均能增加该群体比例。联合治疗方案对细胞增殖影响有限，而单用MK-0752可使SK-LMS-1细胞增殖降低至0.63倍**。无论是单用还是联合用药，MK-0752均能改变基因表达和KEGG通路。综上所述，MK-0752分别与阿霉素、多西他赛或吉西他滨联合多西他赛的方案，可能成为uLMS的新型治疗策略。（*p<0.05, **p<0.01）

原文链接：

Combined Treatment of Uterine Leiomyosarcoma with Gamma Secretase Inhibitor MK-0752 and Chemotherapeutic Agents Decreases Cellular Invasion and Increases Apoptosis