1. Spicamycin and KRN5500 Induce Apoptosis in Myeloid and Lymphoid Cell Lines with Down‐regulation of Bcl‐2 Expression and Modulation of Promyelocytic Leukemia Protein
- Author
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Kazunori Ohnishi, Ryuzo Ohno, Kensuke Naito, Akihiro Takeshita, Farkhad Muratkhodjaev, Kazuyuki Shigeno, Lola Maksumova, Hitoshi Yoshida, Shinya Fujisawa, Satoki Nakamura, Wen Jie Zhang, L Pan, Jian Min Luo, and Kaori Shinjo
- Subjects
Acute promyelocytic leukemia ,Cancer Research ,Programmed cell death ,Myeloid ,Cell Survival ,Cellular differentiation ,Down-Regulation ,Apoptosis ,HL-60 Cells ,Biology ,Promyelocytic Leukemia Protein ,Article ,Promyelocytic leukemia protein ,hemic and lymphatic diseases ,medicine ,Tumor Cells, Cultured ,Humans ,PML ,Antibiotics, Antineoplastic ,Spicamycin ,Tumor Suppressor Proteins ,Bcl‐2 ,Myeloid leukemia ,KRN5500 ,Nuclear Proteins ,Cell Differentiation ,Purine Nucleosides ,medicine.disease ,Hematopoietic Stem Cells ,Virology ,Neoplasm Proteins ,Leukemia ,medicine.anatomical_structure ,Oncology ,Proto-Oncogene Proteins c-bcl-2 ,Cell culture ,Cancer research ,biology.protein ,Transcription Factors - 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.
- Published
- 2000