title: 2-Hydroxypropyl-β-Cyclodextrin Acts as a Novel Anticancer Agent.
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.
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Yokoo
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.|Department of Transfusion Medicine, Saga University Hospital, Saga, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Taniyoshi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tokumaru
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Rena
authors.initials: R
authors.lastname: Nishiyama
authors.affiliation: Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tabe
authors.affiliation: Department of Pharmacy, Saga University Hospital, Saga, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Mochinaga
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Sato
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Sueoka-Aragane
authors.affiliation: Department of Transfusion Medicine, Saga University Hospital, Saga, Japan.|Department of Clinical Laboratory Medicine, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Eisaburo
authors.initials: E
authors.lastname: Sueoka
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.|Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Global Oriented) Program", Kumamoto University, Kumamoto, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.|Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Global Oriented) Program", Kumamoto University, Kumamoto, Japan.
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism; D003124:Colorimetry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008168:Lung / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D047392:beta-Cyclodextrins / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol; D016044:Fusion Proteins, bcr-abl