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

ABSTRACT: 2-Hydroxypropyl-?-cyclodextrin (HP-?-CyD) is a cyclic oligosaccharide that is widely used as an enabling excipient in pharmaceutical formulations, but also as a cholesterol modifier. HP-?-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-?-CyD itself might have anticancer effects. This study provides evidence that HP-?-CyD inhibits leukemic cell proliferation at physiologically available doses. First, we identified the potency of HP-?-CyD in vitro against various leukemic cell lines derived from acute myeloid leukemia (AML), acute lymphoblastic leukemia and chronic myeloid leukemia (CML). HP-?-CyD treatment reduced intracellular cholesterol resulting in significant leukemic cell growth inhibition through G2/M cell-cycle arrest and apoptosis. Intraperitoneal injection of HP-?-CyD significantly improved survival in leukemia mouse models. Importantly, HP-?-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-?-CyD. Systemic administration of HP-?-CyD to mice had no significant adverse effects. These data suggest that HP-?-CyD is a promising anticancer agent regardless of disease or cellular characteristics.

SUBMITTER: Yokoo M 

PROVIDER: S-EPMC4633159 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature