Synergistic antileukemia effect of genistein and chemotherapy in mouse xenograft model and potential mechanism through MAPK signaling.
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.
Shen
Jing
J
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Tai
Yan-Chin
YC
Zhou
Jianbiao
J
Stephen Wong
Ching-Ho
CH
Cheang
Pek Tan S
PT
Fred Wong
Wai-Shiu
WS
Xie
Zhigang
Z
Khan
Matiullah
M
Han
Jin-Hua
JH
Chen
Chien-Shing
CS
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
D003561:Cytarabine; D019833:Genistein