Xanthocillins as thrombopoietin mimetic small molecules.
Four xanthocillins (1-4), including a new compound 4, were isolated from cultured marine fungus Basipetospora sp. as thrombopoietin (TPO) mimics. Compounds 1-4 promoted the proliferation of a TPO-sensitive human leukemia cell line, UT-7/TPO, and UT-7/EPO-mpl, genetically engineered to express c-Mpl, a receptor for TPO in dose-dependent manners. However, the proliferation of UT-7/EPO, a parental cell line of UT-7/EPO-mpl that was devoid of TPO receptor, was not affected by them. Thrombopoietic action of compound 1 was nearly as potent as that of TPO, inducing cell proliferation at a concentration ranging from 1 to 100nM. Compound 1 also induced the phosphorylation of several proteins, including Janus kinase 2 (Jak2), signal transducers, and activators of transcription-3 (STAT3) and STAT5 in the UT-7/EPO-mpl cell line, but not in the UT-7/EPO cell line. These data indicated that xanthocillins are putative agonists for c-Mpl, as their cellular actions were analogous to those of TPO.
Sakai
Ryuichi
R
Kitasato University, School of Fisheries Sciences, Sanriku-cho, Ofunato, Iwate, Japan. r.sakai@kitasato-u.ac.jp
Nakamura
Takanori
T
Nishino
Taito
T
Yamamoto
Masao
M
Miyamura
Atsushi
A
Miyamoto
Hisae
H
Ishiwata
Norihisa
N
Komatsu
Norio
N
Kamiya
Hisao
H
Tsuruzoe
Nobutomo
N
D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology*; D002070:Butadienes / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D053628:Receptors, Thrombopoietin; D015398:Signal Transduction / Q000187:drug effects; D013926:Thrombopoietin / Q000737:chemistry* / Q000494:pharmacology
D002070:Butadienes; D010636:Phenols; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C493153:xantocillin; C082218:MPL protein, human; D013926:Thrombopoietin