title: Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells.
abstract: Treatment with Abl tyrosine kinase inhibitors (TKI) drastically improves the prognosis of chronic myelogenous leukemia (CML) patients. However, quiescent CML cells are insensitive to TKI and can lead to relapse of the disease. Thus, research is needed to elucidate the properties of these quiescent CML cells, including their microenvironment, in order to effectively target them. Hypoxia is known to be a common feature of solid tumors that contributes to therapeutic resistance. Leukemic cells are also able to survive and proliferate in severely hypoxic environments. The hypoxic conditions in the bone marrow (BM) allow leukemic cells that reside there to become insensitive to cell death stimuli. To target leukemic cells in hypoxic conditions, we focused on the hypoxia-selective cytotoxin, Rakicidin A. A previous report showed that Rakicidin A, a natural product produced by the Micromonospora strain, induced hypoxia-selective cytotoxicity in solid tumors. Here, we describe Rakicidin A-induced cell death in hypoxia-adapted (HA)-CML cells with stem cell-like characteristics. Interestingly, apoptosis was induced via caspase-dependent and -independent pathways. In addition, treatment with Rakicidin A in combination with the TKI, imatinib, resulted in synergistic cytotoxicity against HA-CML cells. In conclusion, Rakicidin A is a promising compound for targeting TKI-resistant quiescent CML stem cells in the hypoxic BM environment.
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Eishi
authors.initials: E
authors.lastname: Ashihara
authors.forename: Yohko
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Ruriko
authors.initials: R
authors.lastname: Tanaka
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Yao
authors.forename: Rina
authors.initials: R
authors.lastname: Nagao
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Hideyo
authors.initials: H
authors.lastname: Hirai
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D000222:Adaptation, Physiological; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D019008:Drug Resistance, Neoplasm; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D055666:Lipopeptides / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D047630:Depsipeptides
chemical_list: D000970:Antineoplastic Agents; D053148:Caspase 3; D055666:Lipopeptides; D010456:Peptides, Cyclic; D047428:Protein Kinase Inhibitors; C000723972:rakicidins; D047630:Depsipeptides