International Journal of Molecular Sciences | |
Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells | |
Yuki Kondo1  Yoichi Ishitsuka1  Yusei Yamada1  Tetsumi Irie1  Madoka Fukaura1  Nodoka Sakata1  Sanzana Hoque1  Keiichi Motoyama2  Akio Hayashi3  Takaki Komiya3  Hidetoshi Arima4  Taishi Higashi5  Katsumi Higaki6  | |
[1] Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan;Laboratory of Evidence-based Pharmacotherapy, Daiichi University of Pharmacy, 22-1 Tamagawa-machi, Minami-ku, Fukuoka 815-8511, Japan;Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;Research Initiative Center, Organization for Research Initiative and Promotion, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan; | |
关键词: niemann–pick disease type c; cyclodextrin; 2-hydroxypropyl-β-cyclodextrin; 2-hydroxypropyl-γ-cyclodextrin; miglustat; cholesterol; lysosome; sphingolipid; sphingomyelin; | |
DOI : 10.3390/ijms21030898 | |
来源: DOAJ |
【 摘 要 】
Niemann−Pick disease type C (NPC) is an autosomal recessive disorder characterized by abnormal accumulation of free cholesterol and sphingolipids in lysosomes. The iminosugar miglustat, which inhibits hexosylceramide synthesis, is used for NPC treatment, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic oligosaccharide derivative, is being developed to treat NPC. Moreover, therapeutic potential of 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was shown in NPC models, although its mechanism of action remains unclear. Here, we investigated the effects of HP-β-CD, HP-γ-CD, and their homolog 2-hydroxypropyl-α-cyclodextrin (HP-α-CD) on lipid accumulation in Npc1-null Chinese hamster ovary (CHO) cells compared with those of miglustat. HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced intracellular free cholesterol levels and normalized the lysosome changes in Npc1-null cells but not in wild-type CHO cells. In contrast, miglustat did not normalize intracellular free cholesterol accumulation or lysosome changes in Npc1-null cells. However, miglustat decreased the levels of hexosylceramide and tended to increase those of sphingomyelins in line with its action as a glucosylceramide synthase inhibitor in both Npc1-null and wild-type CHO cells. Interestingly, HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced sphingomyelins in Npc1-null, but not wild-type, cells. In conclusion, HP-β-CD and HP-γ-CD reduce the accumulation of sphingolipids, mainly sphingomyelins, and free cholesterol as well as lysosome changes in Npc1-null, but not in wild-type, CHO cells.
【 授权许可】
Unknown