2-Hydroxypropyl-β-Cyclodextrin Acts as a Novel Anticancer Agent

PLoS One. 2015 Nov 4;10(11):e0141946. doi: 10.1371/journal.pone.0141946. eCollection 2015.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cholesterol / analysis
  • Cholesterol / metabolism
  • Colorimetry
  • Drug Resistance, Neoplasm / drug effects
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myeloid, Acute / drug therapy
  • Lung / pathology
  • M Phase Cell Cycle Checkpoints / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Signal Transduction / drug effects
  • Transplantation, Heterologous
  • beta-Cyclodextrins / therapeutic use
  • beta-Cyclodextrins / toxicity*

Substances

  • Antineoplastic Agents
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Cholesterol
  • Fusion Proteins, bcr-abl

Grants and funding

This work was supported in part by a Grant-in-Aid for Challenging Exploratory Research 25670452 (YK) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan.