Differential cellular responses induced by dorsomorphin and LDN-193189 in chemotherapy-sensitive and chemotherapy-resistant human epithelial ovarian cancer cells
Differential cellular responses induced by dorsomorphin and LDN-193189 in chemotherapy-sensitive and chemotherapy-resistant human epithelial ovarian cancer cells
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DOI：
10.1002/ijc.29220
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发表时间：
2015-03-01
影响因子：
6.4
通讯作者：
Nachtigal, Mark W.
中科院分区：
文献类型：
--
作者：
Ali, Jennifer L.;Lagasse, Brittany J.;Nachtigal, Mark W.
固有或获得性耐药是上皮性卵巢癌（EOC）死亡率的主要原因。产生EOC细胞死亡或使耐药细胞对标准化疗重新敏感的新型药物或药物组合可以改善患者治疗。在对多激酶抑制剂dorsomorphin（DM）及其结构类似物LDN-193189（LDN）进行药物耐受性研究后，在EOC的小鼠腹膜内异种移植模型中测试了这些药物。DM显著增加存活率，而LDN显示出增加存活率的趋势。在体外实验中，使用顺铂（CP）耐药EOC细胞系，A2780-CP或SKOV 3，我们确定了预处理或与DM或LDN共处理使细胞对CP或卡铂（CB）的杀伤作用重新敏感。DM能阻断EOC细胞周期和迁移，而LDN对细胞周期的影响不明显，对迁移无影响。使用原代人EOC细胞样品或另外建立的EOC细胞系的后续分析显示，DM或LDN分别诱导剂量依赖性自噬或细胞死亡应答。DM诱导了特征性形态变化，出现大量含有LC 3B的酸性液泡和LC 3BII水平增加。这与细胞生长减少和细胞周期改变一致，与DM诱导的细胞停滞一致。相比之下，LDN产生了半胱天冬酶3独立的，活性氧依赖性细胞死亡。总的来说，DM和LDN具有适合作为辅助药物用于治疗化疗敏感和耐药EOC的药物特性。在完成初始化疗后的18个月内，多达75%的上皮性卵巢癌（EOC）女性会出现化疗耐药疾病复发。这种现象可以通过发现能够恢复耐药细胞药物敏感性的新疗法来克服。两种这样的药物包括多激酶抑制剂dorsomorphin及其类似物LDN-193189，本文报道了它们在EOC小鼠异种移植模型中增加存活率。这些药物成功地使耐药卵巢癌细胞对铂类药物的杀伤作用重新敏感。机制评估显示，dorsomorphin通常诱导自噬，而LDN-193189诱导细胞凋亡。
Inherent or acquired drug resistance is a major contributor to epithelial ovarian cancer (EOC) mortality. Novel drugs or drug combinations that produce EOC cell death or resensitize drug resistant cells to standard chemotherapy may improve patient treatment. After conducting drug tolerability studies for the multikinase inhibitors dorsomorphin (DM) and it is structural analogue LDN-193189 (LDN), these drugs were tested in a mouse intraperitoneal xenograft model of EOC. DM significantly increased survival, whereas LDN showed a trend toward increased survival. In vitro experiments using cisplatin (CP)-resistant EOC cell lines, A2780-cp or SKOV3, we determined that pretreatment or cotreatment with DM or LDN resensitized cells to the killing effect of CP or carboplatin (CB). DM was capable of blocking EOC cell cycle and migration, whereas LDN produced a less pronounced effect on cell cycle and no effect on migration. Subsequent analyses using primary human EOC cell samples or additional established EOC cells lines showed that DM or LDN induced a dose-dependent autophagic or cell death response, respectively. DM induced a characteristic morphological change with the appearance of numerous LC3B-containing acidic vacuoles and an increase in LC3BII levels. This was coincident with a decrease in cell growth and the altered cell cycle consistent with DM-induced cytostasis. By contrast, LDN produced a caspase 3-independent, reactive oxygen species-dependent cell death. Overall, DM and LDN possess drug characteristics suitable for adjuvant agents used to treat chemotherapy-sensitive and -resistant EOC.What's new? Within 18 months of completing initial chemotherapy, as many as 75% of women with epithelial ovarian cancer (EOC) experience relapse with chemoresistant disease. This phenomenon may be overcome through the discovery of new therapies that are capable of restoring drug sensitivity in resistant cells. Two such agents include the multikinase inhibitor dorsomorphin and its analog LDN-193189, which are reported here to increase survival in a mouse xenograft model of EOC. The agents successfully resensitized drug-resistant ovarian cancer cells to the killing effects of platinum agents. Mechanistic evaluation revealed that dorsomorphin typically induces autophagy, whereas LDN-193189 induces apoptosis.