title: Spicamycin and KRN5500 induce apoptosis in myeloid and lymphoid cell lines with down-regulation of bcl-2 expression and modulation of promyelocytic leukemia protein.
abstract: Spicamycin is a potent inducer of differentiation of human myeloid leukemia cells (HL-60) and murine myeloid leukemia cells (M1). One of the spicamycin derivatives, KRN5500, shows a broad spectrum of antitumor activity against human tumor xenografts in nude mice. In this study, we first investigated the differentiation efficacy of spicamycin and KRN5500 in HL-60 and acute promyelocytic leukemia cell line, NB4, and found that low concentrations of both compounds induced differentiation to a small extent in both cell lines, but markedly induced apoptosis in NB4 cells. Further investigation in a myeloid leukemia cell line, NKM-1, a lymphoma cell line, Daudi, and a multiple myeloma cell line, NOP-1, showed that high concentrations of both compounds also induced apoptosis in these cells. The 50% inhibitory concentration (IC(50)) determined by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that myeloid cells were more sensitive to both compounds than lymphoid cells, and spicamycin was more potent than KRN5500. Western blot analysis of Bcl-2, Bcl-xL and Bax expression and immunofluorescence analysis of promyelocytic leukemia (PML) protein indicated that apoptosis induced by spicamycin and KRN5500 was associated with down-regulation of Bcl-2 expression and modulation of PML protein. Thus, spicamycin and KRN5500 may be useful for the treatment of myeloid and lymphoid neoplasms.
authors.affiliation: Department of Medicine III, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu 431-3192, Japan.
authors.forename: W J
authors.initials: WJ
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Ohnishi
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: L
authors.initials: L
authors.lastname: Pan
authors.forename: L
authors.initials: L
authors.lastname: Maksumova
authors.forename: F
authors.initials: F
authors.lastname: Muratkhodjaev
authors.forename: J M
authors.initials: JM
authors.lastname: Luo
authors.forename: K
authors.initials: K
authors.lastname: Shigeno
authors.forename: S
authors.initials: S
authors.lastname: Fujisawa
authors.forename: K
authors.initials: K
authors.lastname: Naito
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Shinjo
authors.forename: A
authors.initials: A
authors.lastname: Takeshita
authors.forename: R
authors.initials: R
authors.lastname: Ohno
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D011684:Purine Nucleosides / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011684:Purine Nucleosides; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C015502:septacidin; C092296:KRN 5500