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

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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.