Spicamycin and KRN5500 Induce Apoptosis in Myeloid and Lymphoid Cell Lines with Down-regulation of Bcl-2 Expression and Modulation of Promyelocytic Leukemia Protein |
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Authors: | Wen Jie Zhang Kazunori Ohnishi Hitoshi Yoshida Ling Pan Lola Maksumova Farkhad Muratkhodjaev Jian Min Luo Kazuyuki Shigeno Shinya Fujisawa Kensuke Naito Satoki Nakamura Kaori Shinjo Akihiro Takeshita Ryuzo Ohno |
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Institution: | Department of Medicine III, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu 431–3192 |
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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 multiple myeloma cell line, NOP-1, showed that high concentrations of both compounds also induced apoptosis in these cells. The 50% inhibitory concentration (IC50) 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. |
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Keywords: | Spicamycin KRN5500 Apoptosis Bcl-2 PML |
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