Effects of Hibarimicins and Hibarimicin-Related Compounds Produced by Microbispora on v-Src Kinase Activity and Growth and Differentiation of Human Myeloid Leukemia HL-60 Cells

• Published in: Journal of antibiotics 2002/03/25, Vol.55(3), pp.270-278
• Main Authors: CHO, SUNG IG, FUKAZAWA, HIDESUKE, HONMA, YOSHIO, KAJIURA, TAKAYUKI, HORI, HIROSHI, IGARASHI, YASUHIRO, FURUMAI, TAMOTSU, OKI, TOSHIKAZU, UEHARA, YOSHIMASA
• Format: Article
• Language: English
• Subjects: Actinomycetales - metabolism; Anti-Bacterial Agents - biosynthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents; Antineoplastic agents; Applied microbiology; Biological and medical sciences; Cell Differentiation - drug effects; Cell Division - drug effects; Chemotherapic agents; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; General aspects; Glycosides - biosynthesis; Glycosides - chemistry; Glycosides - pharmacology; HL-60 Cells; Humans; Medical sciences; Microbiology; Naphthacenes - chemistry; Naphthacenes - pharmacology; Pharmacology. Drug treatments; src-Family Kinases - antagonists & inhibitors
• ISSN: 0021-8820; 1881-1469
• DOI: 10.7164/antibiotics.55.270

We studied the effects of hibarimicins and hibarimicin-related compounds produced by Microbispora rosea subsp. hibaria [glycosides (hibarimicins A, B, C, D, E, G, H and I) and aglycon (hibarimicinone)] or compounds produced by its mutants [glycosides (HMP-P4 and -Y6), aglycons (HMP-P1 and -Y1) and shunt products (HMP-M1, M2, M3 and -M4)] on v-Src tyrosine kinase and growth and differentiation of human myeloid leukemia HL-60 cells. Among them, hibarimicin B was a strong and the most selective v-Src kinase inhibitor with differentiation inducing activity of HL-60 cells. Hibarimicin E similarly induced HL-60 cell differentiation but had no v-Src kinase inhibitory activity. Hibarimicinone was the most potent v-Src kinase inhibitor, although less selective, and did not induce differentiation of HL-60 cells. Hibarimicin B competitively inhibited ATP binding to the v-Src kinase, but hibarimicinone showed noncompetitive inhibition. These two compounds, however, showed similar mixed types of inhibition against a Src substrate binding to the v-Src kinase. Altogether, these results suggest that signaling molecules other than Src might be more important in the differentiation induction of HL-60 cells.