title: Synergistic effect of AS101 and Bryostatin-1 on myeloid leukemia cell differentiation in vitro and in an animal model.
abstract: We evaluated the synergistic activity of AS101 (ammonium trichloro-(dioxoethylene-0-0')-tellurate) with the protein kinase C (PKC) activators, Bryostatin-1 and phorbol-12-myristate-13-acetate (PMA), on human myelocytic leukemia cell differentiation in vitro, and in a mouse model. Use of AS101 with Bryostatin-1 or with a low concentration of PMA resulted in the differentiation of HL-60 cell line to cells with characteristics of macrophages. A similar synergistic effect was found in vivo. Compared with mice treated with AS101 alone or with Bryostatin-1 alone, the infiltration of leukemic cells into the spleen and the peritoneum of mice treated with both compounds, as well as the number of the HL-60 colonies extracted from those organs, were markedly reduced. The antitumor effects were associated with significantly prolonged survival (100% for 125 days) of the treated mice. Finally, the mechanism of action of this antitumor effect was explored, and was found to involve the Ras/extracellular signal-regulated kinase signaling pathway. Combined treatment with AS101 and Bryostatin-1 synergistically increased p21(waf1) expression levels independently of p53. Upregulation of p21(waf1) was necessary for HL-60 cell differentiation, which was found to be both c-raf-1 and mitogen-activated protein kinase dependent. This study may have implications for the development of strategies to induce differentiation in myeloid leukemias, myelodysplasias and possibly in other malignancies.
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Safdié Institute for AIDS and Immunology Research, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Hayun
authors.forename: E
authors.initials: E
authors.lastname: Okun
authors.forename: R
authors.initials: R
authors.lastname: Hayun
authors.forename: U
authors.initials: U
authors.lastname: Gafter
authors.forename: M
authors.initials: M
authors.lastname: Albeck
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
authors.forename: B
authors.initials: B
authors.lastname: Sredni
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D054713:Bryostatins; D002454:Cell Differentiation / Q000187:drug effects*; D004357:Drug Synergism; D005030:Ethylenes / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018922:HL-60 Cells / Q000637:transplantation; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology*; D018942:Macrolides / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D018631:ras Proteins / Q000378:metabolism
chemical_list: D054713:Bryostatins; D005030:Ethylenes; D018942:Macrolides; C046785:bryostatin 1; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins