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.
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.
Cho
Sung Ig
SI
Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo, Japan.
Fukazawa
Hidesuke
H
Honma
Yoshio
Y
Kajiura
Takayuki
T
Hori
Hiroshi
H
Igarashi
Yasuhiro
Y
Furumai
Tamotsu
T
Oki
Toshikazu
T
Uehara
Yoshimasa
Y
D000192:Actinomycetales / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006027:Glycosides / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D009279:Naphthacenes / Q000737:chemistry / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006027:Glycosides; D009279:Naphthacenes; C456032:hibarimicin B; C456033:hibarimicinone; D019061:src-Family Kinases