Costunolide induces apoptosis in human endometriotic cells through inhibition of the prosurvival Akt and nuclear factor kappa B signaling pathway.
Costunolide induces apoptosis in human endometriotic cells through inhibition of the prosurvival Akt and nuclear factor kappa B signaling pathway.
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DOI：
10.1248/bpb.34.580
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发表时间：
2011-04
影响因子：
2
通讯作者：
Ji-Hyun Kim;Yeong-In Yang;Kyung-Tae Lee;Hee-Juhn Park;Jung-Hye Choi
中科院分区：
文献类型：
--
作者：
Ji-Hyun Kim;Yeong-In Yang;Kyung-Tae Lee;Hee-Juhn Park;Jung-Hye Choi
子宫内膜异位症是一种影响5-15%育龄妇女的疾病，其特征在于子宫内膜组织的异位生长。木香烯酮是一种倍半萜内酯，具有抗增殖和促凋亡活性，可有效治疗子宫内膜异位症。在本研究中，我们研究了木香烃内酯对子宫内膜异位症细胞生长和凋亡的影响。我们发现，costunelinate显着抑制11 Z和12 Z人上皮细胞的细胞活力。有趣的是，子宫内膜异位细胞比永生化子宫内膜细胞（HES）对考司坦治疗更敏感。COSTUNDIUM诱导11 Z细胞凋亡的时间依赖性的方式所示的积累的亚G1群体。此外，用costunlide处理以剂量和时间依赖性方式诱导半胱天冬酶-3、-8和-9的活化。用广泛的caspase抑制剂z-VAD-favorite预处理显著逆转了木香烃内酯诱导的11 Z细胞活力抑制。我们进一步证明，木香酮抑制Akt和核因子κ B（NFκB）的活化以及抗凋亡因子B细胞淋巴瘤外拉格（Bcl-xL）和X连锁凋亡抑制蛋白（XIAP）在11 Z细胞中的表达。这些结果表明，木香酮通过抑制NFκB和Akt通路，下调抗凋亡蛋白Bcl-xL和XIAP的表达，激活caspase，从而诱导人上皮细胞凋亡。
Endometriosis, a disease affecting 5-15% of women of reproductive age, is characterized by the ectopic growth of endometrial tissue. Costunolide, a sesquiterpene lactone, has anti-proliferative and pro-apoptotic activities that may be efficacious in therapy for endometriosis. In the present study, we investigated the effect of costunolide on the cell growth and apoptosis of endometriotic cells. We found that costunolide significantly inhibited the cell viability of 11Z and 12Z human endometriotic epithelial cells. Interestingly, endometriotic cells were more sensitive to costunolide treatment than immortalized endometrial cells (HES). Costunolide induced apoptosis of 11Z cells in a time-dependent manner as shown by accumulation of sub-G1 population. In addition, treatment with costunolide induced the activation of caspase-3, -8, and -9 in a dose- and time-dependent manner. Pretreatment with the broad caspase inhibitor z-VAD-fmk significantly reversed the costunolide-induced inhibition of cell viability in 11Z cells. We further demonstrated that costunolide inhibited the activation of Akt and nuclear factor kappa B (NFκB) and the expression of anti-apoptotic factors B-cell lymphoma-extra lage (Bcl-xL) and X-linked inhibitor of apoptosis protein (XIAP) in 11Z cells. These results suggest that costunolide induces apoptosis in human endometriotic epithelial cells by inhibiting the prosurvival NFκB and Akt pathway, leading to the downregulation of anti-apoptotic protein Bcl-xL and XIAP and the activation of caspases.