Induction of apoptosis of RAW 264.7 cells by the cytostatic macrolide apicularen A.
In RAW 264.7 cells, a mouse leukaemic monocyte cell line, apicularen A decreased cell growth and survival as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in a concentration-dependent manner at 10-1000 nM. Apicularen B, an N-acetyl-glucosamine glycoside of apicularen A, was 10-100-fold less effective than apicularen A. Apicularen A induced a DNA ladder, an increase in the percentage of sub-G(1) cells and annexin V-binding cells, and promoted the activation of caspase as revealed by the cleavage of poly(ADP-ribose) polymerase, indicating that apicularen A induced apoptosis in RAW 264.7 cells. In addition, apicularen A phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK. The p44/42 MAPK inhibitor PD98059 rescued the cells from apicularen-induced decrease in cell growth and survival as determined by the MTT assay, while the p38 MAPK inhibitor SB203580 augmented the effect of apicularen A. This suggested the activation of p44/42 MAPK to be pro-apoptotic and the activation of p38 MAPK antiapoptotic in apicularen A-treated RAW 264.7 cells.
Hong
JangJa
J
Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba Aramaki, Aobaku, Sendai, Miyagi, Japan.
Yamaki
Kouya
K
Ishihara
Kenji
K
Ahn
Jong Woong
JW
Zee
OkPyo
O
Ohuchi
Kazuo
K
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009930:Organic Chemicals / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D007093:Imidazoles; D018942:Macrolides; D009930:Organic Chemicals; C466090:PD 98058; D011725:Pyridines; C117813:apicularen A; C117814:apicularen B; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; C093642:SB 203580