Spicamycin and KRN5500 Induce Apoptosis in Myeloid and Lymphoid Cell Lines with Down‐regulation of Bcl‐2 Expression and Modulation of Promyelocytic Leukemia Protein

• Published in: Cancer science Vol. 91; no. 6; pp. 604 - 611
• Main Authors: Zhang, Wen Jie, Ohnishi, Kazunori, Yoshida, Hitoshi, Pan, Ling, Maksumova, Lola, Muratkhodjaev, Farkhad, Luo, Jian Min, Shigeno, Kazuyuki, Fujisawa, Shinya, Naito, Kensuke, Nakamura, Satoki, Shinjo, Kaori, Takeshita, Akihiro, Ohno, Ryuzo
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-06-2000; Japanese Cancer Association; John Wiley & Sons, Inc
• Subjects: Acute promyeloid leukemia; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Antitumor activity; Apoptosis; Apoptosis - drug effects; Bax protein; Bcl‐2; Biological and medical sciences; Cell differentiation; Cell Differentiation - drug effects; Cell Survival - drug effects; Down-Regulation - drug effects; General aspects; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; HL-60 Cells - cytology; HL-60 Cells - drug effects; HL-60 Cells - metabolism; Humans; Immunofluorescence; KRN5500; Leukemia; Lymphoid cell lines; Lymphoid cells; Lymphoma; Medical sciences; Multiple myeloma; Myeloid cells; Myeloid leukemia; Neoplasm Proteins - biosynthesis; Nuclear Proteins; Pharmacology. Drug treatments; PML; PML protein; Promyelocytic Leukemia Protein; Promyeloid leukemia; Proteins; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Purine Nucleosides - pharmacology; Spicamycin; Transcription Factors - biosynthesis; Tumor Cells, Cultured; Tumor Suppressor Proteins; Xenografts; Antineoplastic agent; Human; Promyelocytic leukemia; Immunopathology; Acute; Malignant hemopathy; Cell differentiation; Gene expression; Non Hodgkin lymphoma; Myeloma; In vitro; HL60 cell line; Antibiotic; Regulation(control); Immunoglobulinopathy; Cell death; Lymphoproliferative syndrome; Analog; C-Onc gene; Established cell line; Genetics; Protooncogene; Apoptosis; Acute myelocytic leukemia
• ISSN: 0910-5050; 1347-9032; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.2000.tb00988.x

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.