In vitro evaluation of 2-hydroxyalkylated ß-cyclodextrins as potential therapeutic agents for Niemann-Pick Type C disease.

This study was conducted to evaluate the attenuating potential of 2-hydroxypropyl-ß-cyclodextrin (HPBCD) against Niemann-Pick Type C (NPC) disease, as well as the physical and chemical properties, particularly the cholesterol-solubilizing ability, in an NPC disease model in vitro. As parameters of NPC abnormalities, intracellular free and esterified cholesterol levels and lysosome volume were measured in Npc1 null Chinese hamster ovary cells. HPBCD showed dose-dependent effects against dysfunctional intracellular cholesterol trafficking, such as the accumulation and shortage of free and esterified cholesterols, respectively, in Npc1 null cells. However, the effectiveness was gradually offset by exposure to ≥8mM HPBCD. The same effect was also observed for increasing lysosome volume in Npc1 null cells. The degree of substitution of the hydroxypropyl group had little influence on the attenuating effects of HPBCD against the NPC abnormalities, at least in the range between 2.8 and 7.4. Next, we compared the effects of other hydroxyalkylated ß-cyclodextrin derivatives with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-ß-cyclodextrin (HEBCD) and 2-hydroxybutyl-ß-cyclodextrin (HBBCD). The cholesterol solubilizing potential, attenuating effects against NPC abnormalities and cytotoxicity induction were HBBCD≫HPBCD>HEBCD, HBBCD=HPBCD>HEBCD and HBBCD≫HPBCD=HEBCD, respectively. HPBCD may be superior in terms of safety and efficacy in Npc1 null cells compared with HEBCD and HBBCD. The results of this study will provide a rationale for the optimization of HPBCD therapy for NPC disease.

2-Hydroxypropyl-ß-Cyclodextrin Acts as a Novel Anticancer Agent.

2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CyD) is a cyclic oligosaccharide that is widely used as an enabling excipient in pharmaceutical formulations, but also as a cholesterol modifier. HP-ß-CyD has recently been approved for the treatment of Niemann-Pick Type C disease, a lysosomal lipid storage disorder, and is used in clinical practice. Since cholesterol accumulation and/or dysregulated cholesterol metabolism has been described in various malignancies, including leukemia, we hypothesized that HP-ß-CyD itself might have anticancer effects. This study provides evidence that HP-ß-CyD inhibits leukemic cell proliferation at physiologically available doses. First, we identified the potency of HP-ß-CyD in vitro against various leukemic cell lines derived from acute myeloid leukemia (AML), acute lymphoblastic leukemia and chronic myeloid leukemia (CML). HP-ß-CyD treatment reduced intracellular cholesterol resulting in significant leukemic cell growth inhibition through G2/M cell-cycle arrest and apoptosis. Intraperitoneal injection of HP-ß-CyD significantly improved survival in leukemia mouse models. Importantly, HP-ß-CyD also showed anticancer effects against CML cells expressing a T315I BCR-ABL mutation (that confers resistance to most ABL tyrosine kinase inhibitors), and hypoxia-adapted CML cells that have characteristics of leukemic stem cells. In addition, colony forming ability of human primary AML and CML cells was inhibited by HP-ß-CyD. Systemic administration of HP-ß-CyD to mice had no significant adverse effects. These data suggest that HP-ß-CyD is a promising anticancer agent regardless of disease or cellular characteristics.