PDF(Pubmed)
Abstract：
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：
由于子宫平滑肌肉瘤（uLMS）的有效治疗方法有限，在uLMS中探讨了γ分泌酶抑制剂（GSI）MK-0752与普通化疗药物的影响。在两种人uLMS细胞系上进行MTT测定，SK-UT-1B和SK-LMS-1，使用MK-0752，多西他赛，阿霉素,和吉西他滨,单独和组合，以确定处理后的细胞活力。协同组合用于transwell侵袭测定，细胞周期流式细胞术，增殖试验,和RNA测序。在SK-UT-1B中，MK-0752与多柔比星和吉西他滨加多西他赛具有协同作用。在SK-LMS-1中,MK-0752与所有单独的药剂以及与吉西他滨加多西他赛的组合具有协同作用。MK-0752,吉西他滨,多西他赛在SK-UT-1B中的侵袭减少2.1倍*，在SK-LMS-1中的侵袭减少1.7倍*。在SK-LMS-1中，用MK-0752和多西他赛治疗后，侵袭性降低了1.2倍*，用MK-0752和阿霉素治疗后降低了2.2倍*。细胞周期分析表明，在SK-UT-1B（1.4倍*）和SK-LMS-1（2.7倍**）中单独使用MK-0752的凋亡亚G1群体增加，随着两种细胞系中所有组合的增加。联合治疗对增殖的影响有限，而MK-0752单独降低SK-LMS-1的增殖(0.63倍**)。MK-0752单独和组合改变了基因表达和KEGG途径。总之,MK-0752与阿霉素的组合，多西他赛,或吉西他滨联合多西他赛是治疗uLMS的潜在新方法。(*p<0.05,**p<0.01)。
