title: Synergistic antileukemia effect of genistein and chemotherapy in mouse xenograft model and potential mechanism through MAPK signaling.
abstract: We investigated the antiproliferative effect of genistein, and its antileukemia effect in combination with cytosine arabinoside (ara-C) in acute myeloid leukemia (AML). Optimal dosage of genistein as single agent and in combination with ara-C was first determined in vitro. Genistein demonstrated a dose- and time-dependent inhibition of cell proliferation, induction of apoptosis, and cell-cycle arrest at G(2)/M phase. Gene-expression profiles revealed mitogen-activated protein kinase (MAPK) signaling as one of the most affected biological pathways. Phosphatidylinositol 3 kinase, protein kinase A, protein kinase C, MAPK kinase 4, KIT, PIM1, and transforming growth factor-beta receptor 1, were significantly downregulated by genistein. To test whether genistein could augment the antiproliferation activity of ara-C, two groups of severe combined immunodeficient mice were inoculated with NB4 and HL-60 cells, respectively, followed by treatment with either genistein or combination of genistein and ara-C. The combination treatment significantly inhibited tumor growth, and improved survival of NB4 (p = 0.0031) and HL-60 (p = 0.0007) xenograft mice. Our present study highlighted the schedule-dependent synergistic antileukemia effect of genistein with chemotherapy in both in vitro and in vivo models. This novel combination could potentially be a promising regimen for treatment of AML.
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.forename: Yan-Chin
authors.initials: YC
authors.lastname: Tai
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zhou
authors.forename: Ching-Ho
authors.initials: CH
authors.lastname: Stephen Wong
authors.forename: Pek Tan S
authors.initials: PT
authors.lastname: Cheang
authors.forename: Wai-Shiu
authors.initials: WS
authors.lastname: Fred Wong
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xie
authors.forename: Matiullah
authors.initials: M
authors.lastname: Khan
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Han
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy; D015996:Survival Rate; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D003561:Cytarabine; D019833:Genistein