Studies on roles of poly (ADP-ribosyl) ation reaction in cell differentiation and programd cell death

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(1) Discovery of poly (ADP-ribose) synthetase inhibitors : From an extensive survey of the synthetase inhibitors among various natural compounds and therapeutic drugs, we found many compounds to exhibit the inhibitory effect to a moderate degree (IC_<50>=1muM-1mM). They include heterocyclic amines produced from amino acids by pyrolysis, and derivatives of coumarine, chromone, phospholipids and vesnarinone (Arkin-Z^<TM>).(2) Induction of cancer cell differentiation by poly (ADP-ribose) inhibitors : Benzylvesnarinone and PhIP,that is an abundant heterocyclic amine in food, were found to induce most efficiently the neuronal differentiation of teratocarcinoma EC cells in culture.(3) Changes in poly (ADP-ribose) metabolism in differentiation-induced cells : Poly (ADP-ribose) synthesis was found to increase transiently at the very early stage (within 1 day) of teratocarcinoma EC cell differentiation induced by all-trans-retrinoic acid.This finding, unlike the current view of monotonous inactivation of poly (ADP-ribose) synthesis, suggested a possible involvement of DNA fragmentation and its regulation by poly (ADP-ribose) in the initiation of cell differentiation.