Genistein induces G2 arrest in malignant B cells by decreasing IL-10 secretion.
Chronic B cell malignancies are often chemoresistant and the development of new therapeutic modalities is a high priority. Many B cell malignancies have autocrine production of IL-10, which regulates B cell growth and differentiation. Here we demonstrate that the soy isoflavone genistein, a tyrosine kinase inhibitor, rapidly decreased IL-10 secretion followed by upregulation of IFNgamma and inhibition of cell proliferation with pre-dominantly G2 arrest. The antiproliferative effects of genistein were reversed by the addition of exogenous IL-10. Genistein downregulated cdc25C and cdk1 as well as anti-apoptotic proteins survivin and Ian-5. After genistein withdrawal, the G2M arrested cells reentered the cell cycle and underwent apoptosis, which was significantly augmented by fludarabine. We conclude that genistein can sensitize malignant B cells to the action of other chemotherapeutic agents by modulating the cytokine profile and controlling cell cycle progression.
Mansour
Amal
A
New Jersey Medical School, UMDNJ, Newark, New Jersey 07103, USA.
McCarthy
Brian
B
Schwander
Stephan K
SK
Chang
Victor
V
Kotenko
Sergei
S
Donepudi
Sreekrishna
S
Lee
Janet
J
Raveche
Elizabeth
E
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053701:Receptors, Interleukin-10; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D007371:Interferon-gamma; D019833:Genistein; D014740:Vidarabine; C024352:fludarabine