Analysis of the actions and the action mechanism of DIF, an anti-tumor agent isolated from a soil microorganism

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The cellular slime mould Dictyostelium discoideum is thought to be an excellent model organism for the study of cell and developmental biology because of its simple pattern of development. The differentiation-inducing factor-1(DIF-1) was originally identified as signal molecules that induce stalk cell differentiation in D.discoideum. On the other hand, we have shown that DIF-1 exhibits strong anti-proliferative activities and occasionally induce cell differentiation in mammalian cells. Yet, the mechanisms underlying the actions of DIF-1 in mammalian cells remain to be elucidated.In the present study, we have shown that ;1)DIF-1 inactivates STAT3 in gastric cancer cells via MEK/ERK pathway (Kanai et al.2003),2)DIF-1 inhibits the expression of cyclins D/E and the phosphorylation of retinoblastoma protein (pRb) in K562 cells (Akaishi et al.2004), and3)calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is a pharmacological and specific target of DIF-1 (Shimizu et al.2004).4)Furthermore, in order to assess the chemical structure-effect relationship of DIF derivatives and to develop useful agents, we synthesized many analogues of DIF-1 and investigated their stalk-cell-inducing activity anti-proliferative activity in human leukemia K562 cells. We have then found some potent anti-leukemic agents (submitted).5)During the course of this study, we happened to found that zinc ions inhibit calcineurin activity in vitro (Takahashi et al.2003).