Hederagenin potentiated cisplatin- and paclitaxel-mediated cytotoxicity by impairing autophagy in lung cancer cells
Hederagenin potentiated cisplatin- and paclitaxel-mediated cytotoxicity by impairing autophagy in lung cancer cells
复制标题
常春藤素通过损害肺癌细胞的自噬增强顺铂和紫杉醇介导的细胞毒性
DOI：
10.1038/s41419-020-02880-5
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发表时间：
2020-08-13
影响因子：
9
通讯作者：
Xiao, Jianyong
中科院分区：
文献类型：
--
作者：
Wang, Kun;Liu, Xiaodong;Xiao, Jianyong
抑制自噬已被证明可以提高传统化疗的疗效。在这项研究中，我们确定Hederagenin，一种从Hedera helix中提取的三萜类化合物，是一种有效的自噬抑制物，然后假设Hederagenin可能与化疗药物(如顺铂和紫杉醇)协同作用来杀死肺癌细胞。首先，我们观察到Hederagenin诱导肺癌细胞自噬小体增加的同时，伴随着Lc3-II和p62的上调，这表明自噬通量的损害。共定位实验表明，Hederagenin不能阻止溶酶体和自噬小体的融合，而酸性敏感试剂(LysoTracker和丫啶橙)染色减少表明Hederagenin可能抑制溶酶体的酸化。异常的酸性环境损害了溶酶体的功能，表现为成熟组织蛋白酶B和组织蛋白酶D的减少。最后，Hederagenin与我们的假设一致，促进了顺铂和紫杉醇的促凋亡作用，并积累了活性氧(ROS)；而这种协同作用可被ROS清除剂N-乙酰-L-半胱氨酸所消除。这些数据概括地表明，Hederagenin通过阻断自噬通量而导致ROS的积累，增强了顺铂和紫杉醇对肺癌细胞的细胞毒作用。
Autophagy inhibition has been demonstrated to increase the efficacy of conventional chemotherapy. In this study, we identified hederagenin, a triterpenoid derived fromHedera helix, as a potent inhibitor of autophagy and then hypothesized that hederagenin might synergize with chemotherapeutic drugs (e.g., cisplatin and paclitaxel) to kill lung cancer cells. Firstly, we observed that hederagenin induced the increased autophagosomes in lung cancer cells concomitantly with the upregulation of LC3-II and p62, which indicated the impairment of autophagic flux. The colocalization assay indicated hederagenin could not block the fusion of lysosomes and autophagosomes, whereas the lysosomal acidification might be inhibited by hederagenin as revealed by the reduced staining of acidity-sensitive reagents (i.e., Lysotracker and acridine orange). The aberrant acidic environment then impaired the function of lysosome, which was evidenced by the decrease of mature cathepsin B and cathepsin D. Lastly, hederagenin, in agree with our hypothesis, promoted pro-apoptotic effect of cisplatin and paclitaxel with the accumulation of reactive oxygen species (ROS); while the synergistic effect could be abolished by the ROS scavenger, N-acetyl-L-cysteine. These data summarily demonstrated hederagenin-induced accumulation of ROS by blocking autophagic flux potentiated the cytotoxicity of cisplatin and paclitaxel in lung cancer cells.