title: Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome-Positive Lymphoid Leukemia.
abstract: S-phase progression of the cell cycle is accelerated in tumors through various genetic abnormalities, and, thus, pharmacologic inhibition of altered cell-cycle progression would be an effective strategy to control tumors. In the current study, we analyzed the antileukemic activity of three available small molecules targeting CDK4/CDK6 against lymphoid crisis of chronic myeloid leukemia (CML-LC) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL), and found that all three molecules showed specific activities against leukemic cell lines derived from CML-LC and Ph(+) ALL. In particular, PD0332991 exhibited extremely high antileukemic activity against CML-LC and Ph(+) ALL cell lines in the nanomolar range by the induction of G0-G1 arrest and partially cell death through dephosphorylation of pRb and downregulation of the genes that are involved in S-phase transition. As an underlying mechanism for favorable sensitivity to the small molecules targeting CDK4/CDK6, cell-cycle progression of Ph(+) lymphoid leukemia cells was regulated by transcriptional and posttranscriptional modulation of CDK4 as well as Cyclin D2 gene expression under the control of BCR-ABL probably through the PI3K pathway. Consistently, the gene expression level of Cyclin D2 in Ph(+) lymphoid leukemia cells was significantly higher than that in Ph(-) lymphoid leukemia cells. Of note, three Ph(+) ALL cell lines having the T315I mutation also showed sensitivity to PD0332991. In a xenograft model, PD0332991, but not imatinib, suppressed dissemination of Ph(+) ALL having the T315I mutation and prolonged survival, demonstrating that this reagent would be a new therapeutic modality for relapsed CML-LC and Ph(+) ALL patients after treatment with tyrosine kinase inhibitors.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nemoto
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saida
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Kato
authors.affiliation: Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kikuchi
authors.affiliation: Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: Department of Hematology, National Hospital Organization, Osaka Minami Medical Center, Osaka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Akahane
authors.affiliation: Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Honna-Oshiro
authors.affiliation: Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Goi
authors.affiliation: Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kagami
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
authors.affiliation: Adult Nursing, The Japanese Red Cross College of Nursing, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Hematology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Okabe
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Niwa
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
authors.affiliation: Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Sugita
authors.affiliation: Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan. tinukai@yamanashi.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inukai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056742:Cyclin D2; D019941:Cyclin-Dependent Kinase Inhibitor p16; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D016044:Fusion Proteins, bcr-abl; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib