Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan.
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan.
Mar Drugs. 2017 Oct 20;15(10):320. doi: 10.3390/md15100320.
Neopeltolide, an antiproliferative marine macrolide, is known to specifically inhibit complex III of the mitochondrial electron transport chain (mETC). However, details of the biological mode-of-action(s) remain largely unknown. This work demonstrates potent cytotoxic activity of synthetic neopeltolide analogue, 8,9-dehydroneopeltolide (8,9-DNP), against starved human pancreatic adenocarcinoma PANC-1 cells and human non-small cell lung adenocarcinoma A549 cells. 8,9-DNP induced rapid dissipation of the mitochondrial membrane potential and depletion of intracellular ATP level in nutrient-deprived medium. Meanwhile, in spite of mTOR inhibition under starvation conditions, impairment of cytoprotective autophagy was observed as the lipidation of LC3-I to form LC3-II and the degradation of p62 were suppressed. Consequently, cells were severely deprived of energy sources and underwent necrotic cell death. The autophagic flux inhibited by 8,9-DNP could be restored by glucose, and this eventually rescued cells from necrotic death. Thus, 8,9-DNP is a potent anti-austerity agent that impairs mitochondrial ATP synthesis and cytoprotective autophagy in starved tumor cells.
新杀霉素是一种具有抗增殖作用的海洋大环内酯类化合物，已知其可特异性抑制线粒体电子传递链复合体 III（mETC）。然而，其确切的生物学作用机制仍知之甚少。本研究表明，合成的新杀霉素类似物 8,9-脱水新杀霉素（8,9-DNP）对饥饿的人胰腺腺癌细胞 PANC-1 和人非小细胞肺癌 A549 细胞具有很强的细胞毒性。8,9-DNP 在营养缺乏的培养基中可迅速导致线粒体膜电位耗散和细胞内 ATP 水平下降。同时，尽管在饥饿条件下 mTOR 受到抑制，但观察到细胞保护性自噬受损，因为 LC3-I 向 LC3-II 的脂质化和 p62 的降解受到抑制。结果，细胞严重缺乏能源，并发生坏死性细胞死亡。8,9-DNP 抑制的自噬流可通过葡萄糖恢复，这最终使细胞免于坏死性死亡。因此，8,9-DNP 是一种有效的抗饥饿剂，可破坏饥饿肿瘤细胞中线粒体 ATP 的合成和细胞保护性自噬。
