Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan.
Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan.
J Control Release. 2018 Apr 10;275:20-31. doi: 10.1016/j.jconrel.2018.02.010. Epub 2018 Feb 8.
Autophagy plays a pivotal role in the development and prevention of numerous diseases, and the induction of autophagy is regarded as a potential therapeutic approach for intractable diseases. In this study, the induction of autophagy by methylated β-cyclodextrins (Me-β-CDs)-threaded acid-labile polyrotaxane (Me-PRX) that can release the threaded Me-β-CDs in response to acidic pH in lysosomes was investigated. We hypothesized that the Me-β-CDs released from the Me-PRX interact with the membrane of organelles and cause autophagy. The Me-PRX preferentially accumulated in endoplasmic reticulum (ER) and caused ER stress, which was confirmed by gene expression analysis and the expression of an ER stress-marker protein. Accompanying the ER stress, cells treated with Me-PRX showed autophagy, which was not observed in cells treated with non-labile Me-PRX, other chemically modified PRXs, or free Me-β-CD. Furthermore, the Me-PRX treatment induced autophagic cell death and caused cell death even in apoptosis-resistant cells. Overall, this study demonstrates that the acid-labile Me-PRX induces ER stress-mediated autophagic cell death, and the Me-PRX would be a promising candidate to induce effective cell death in apoptosis-resistant malignant tumors.
自噬在许多疾病的发生和防治中起着关键作用，诱导自噬被认为是治疗难治性疾病的一种潜在方法。在这项研究中，研究了酸性溶酶体中可以响应酸性 pH 值释放被甲基化β-环糊精（Me-β-CDs）穿入的酸不稳定聚轮烷（Me-PRX）诱导自噬的能力。我们假设从 Me-PRX 中释放的 Me-β-CDs 与细胞器的膜相互作用并引起自噬。Me-PRX 优先在内质网（ER）中积累并引起 ER 应激，这通过基因表达分析和 ER 应激标志物蛋白的表达得到证实。伴随 ER 应激，用 Me-PRX 处理的细胞表现出自噬，而用非不稳定 Me-PRX、其他化学修饰的 PRX 或游离 Me-β-CD 处理的细胞则没有观察到自噬。此外，Me-PRX 处理诱导自噬性细胞死亡，甚至在抗凋亡细胞中也能引起细胞死亡。总的来说，这项研究表明，酸不稳定的 Me-PRX 诱导 ER 应激介导的自噬性细胞死亡，Me-PRX 可能是诱导抗凋亡恶性肿瘤有效细胞死亡的有前途的候选物。
