Search for novel anti-tumor drugs and study on the action mechanism

分化诱导因子-1(DIF-1)是一种信号分子，在细胞黏液霉菌Dctyostelialdiscoideum中诱导茎细胞分化。另一方面，研究表明，DIF-1具有抗肿瘤活性，抑制细胞生长(G1期停滞)，诱导细胞分化或细胞分化，并诱导细胞凋亡，这取决于药物的浓度。本课题的研究结果如下：i)DIF-1诱导的K562白血病细胞生长停滞与ERK1/2活性降低有关；ii)钙调素依赖的环核苷酸磷酸二酯酶(brefelamide(4-methyl-5-n-propylbenzene-1，3-diol)，)是DIF-1的药理特异性靶点；iii)Dictyopyrones是从Dctyostelialspp.中分离得到的一种新的α-咯烷酮类化合物，能促进盘状网柄菌柄细胞的分化。细胞黏菌对星形细胞瘤细胞的增殖有抑制作用。v)从蜜环菌和硫化乳杆菌成熟的子实体中分离到新的DIF-1样因子。

The differentiation-inducing factor-1 (DIF-1) is a signal molecule that induces stalk cell differentiation in the cellular slime mold Dctyostelium discoideum. On the other hand, it has been shown that DIF-1 exhibits anti-tumor activities, inhibition of cell growth (G1 arrest) and induction of cell differentiation or cell differentiation, and induction of apotosis, depending on the concentration of the drug. But the precise signaling system of DIF-1, including the target molecule(s), has been unknown.The results obtained in this project were as follows :i) DIF-1-induced growth arrest of K562 leukemia cells involved the reduction of ERK 1/2 activity.ii) Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) was a pharmacological specific target of DIF-1.iii) Dictyopyrones, novel α-pyronoids isolated from Dctyostelium spp., promoted stalk cell differentiation in Dctyostelium discoideum.iv) A new aromatic compound, brefelamide(4-methyl-5-n-propylbenzene-1,3-diol), from Dicyostelium cellular slime molds showed the inhibitory effect on the proliferation of astrocytoma cells.v) New DIF-1 like factors were isolated from mature fruiting bodies of Armillaria tabescens and Laetiporus sulphureus.