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: W J Zhang, K Ohnishi, H Yoshida, L Pan, L Maksumova, F Muratkhodjaev, J M Luo, K Shigeno, S Fujisawa, K Naito, S Nakamura, K Shinjo, A Takeshita, R Ohno
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 91 Issue 6 Pg. 604-11 (Jun 2000) ISSN: 0910-5050 [Print] Japan
• PMID: 10874212 (Publication Type: Journal Article)

Chemical References

• Antibiotics, Antineoplastic
• Neoplasm Proteins
• Nuclear Proteins
• Promyelocytic Leukemia Protein
• Proto-Oncogene Proteins c-bcl-2
• Purine Nucleosides
• Transcription Factors
• Tumor Suppressor Proteins
• PML protein, human
• septacidin
• KRN 5500

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• Cell Survival (drug effects)
• Down-Regulation (drug effects)
• HL-60 Cells (cytology, drug effects, metabolism)
• Hematopoietic Stem Cells (cytology, drug effects, metabolism)
• Humans
• Neoplasm Proteins (biosynthesis)
• Nuclear Proteins
• Promyelocytic Leukemia Protein
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, genetics)
• Purine Nucleosides (pharmacology)
• Transcription Factors (biosynthesis)
• Tumor Cells, Cultured
• Tumor Suppressor Proteins