Elaiophylin, a novel autophagy inhibitor, exerts antitumor activity as a single agent in ovarian cancer cells
Elaiophylin, a novel autophagy inhibitor, exerts antitumor activity as a single agent in ovarian cancer cells
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Elaiophylin 是一种新型自噬抑制剂，作为单一药物在卵巢癌细胞中发挥抗肿瘤活性。
DOI：
10.1080/15548627.2015.1017185
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发表时间：
2015-10-01
期刊：
影响因子：
13.3
通讯作者：
Ma, Ding
中科院分区：
文献类型：
--
作者：
Zhao, Xuejiao;Fang, Yong;Ma, Ding
目前，靶向自噬通路被认为是发现癌症药物的一个有前途的新策略。本研究利用GFP-LC 3B-SKOV 3细胞筛选华北制药集团公司微生物来源的纯化合物库，并鉴定了elaiophylin作为一种新型的自噬抑制剂。Elaiophylin促进自噬体积累，但通过减弱溶酶体组织蛋白酶活性来阻断自噬通量，导致SQSTM 1/p62在各种细胞系中积累。此外，如LysoTracker Red染色和CTSB/组织蛋白酶B和CTSD/组织蛋白酶D从溶酶体释放到细胞质中所示，榄叶素使溶酶体不稳定。Elaiophylin最终降低细胞活力，特别是与顺铂组合或在缺氧条件下。此外，在具有转移的原位卵巢癌模型中，施用较低剂量（2 mg/kg）的榄叶素作为单一药剂实现了显著的抗肿瘤作用而没有毒性;然而，高剂量（8 mg/kg）的榄叶素导致潘氏细胞功能障碍，其类似于ATG 16 L1缺陷小鼠的肠表型。总之，这些结果为该化合物的潜在临床应用提供了安全的治疗窗口。我们的研究结果首次表明，elaiophylin是一种新型的自噬抑制剂，作为单一药物或组合在人卵巢癌细胞中具有显著的抗肿瘤功效，从而建立了这种化合物对卵巢癌的潜在治疗。
Currently, targeting the autophagic pathway is regarded as a promising new strategy for cancer drug discovery. Here, we screened the North China Pharmaceutical Group Corporation's pure compound library of microbial origin using GFP-LC3B-SKOV3 cells and identified elaiophylin as a novel autophagy inhibitor. Elaiophylin promotes autophagosome accumulation but blocks autophagic flux by attenuating lysosomal cathepsin activity, resulting in the accumulation of SQSTM1/p62 in various cell lines. Moreover, elaiophylin destabilizes lysosomes as indicated by LysoTracker Red staining and CTSB/cathepsin B and CTSD/ cathepsin D release from lysosomes into the cytoplasm. Elaiophylin eventually decreases cell viability, especially in combination with cisplatin or under hypoxic conditions. Furthermore, administration of a lower dose (2 mg/kg) of elaiophylin as a single agent achieves a significant antitumor effect without toxicity in an orthotopic ovarian cancer model with metastasis; however, high doses (8 mg/kg) of elaiophylin lead to dysfunction of Paneth cells, which resembles the intestinal phenotype of ATG16L1-deficient mice. Together, these results provide a safe therapeutic window for potential clinical applications of this compound. Our results demonstrate, for the first time, that elaiophylin is a novel autophagy inhibitor, with significant antitumor efficacy as a single agent or in combination in human ovarian cancer cells, establishing the potential treatment of ovarian cancer by this compound.