DUAL EFFECTS OF NORDIDEMNIN ON WRK(1) CELLS - INHIBITION OF PHOSPHOINOSITIDE METABOLISM AND CELL-PROLIFERATION

Nordidemnin (NorD), a cyclodepsipeptide isolated from marine invertebr ates, exhibits antiproliferative and antitumoral properties identical to didemnin B on many cell lines. On WRK(1) cells, a rat mammary tumor cell line, NorD considerably reduced the vasopressin-stimulated accum ulation of inositol phosphates. This effect was more pronounced on div iding cells and of weak amplitude on quiescent ones. It was observed w ith nanomolar concentrations of NorD and became significative after 3 hr of incubation at 37 degrees C. The maximal effect was observed afte r a 14-hr incubation period. In contrast, the inactive analog epinordi demnin, as well as the structurally related immunosuppressive cyclospo rin A, had no significant effect on phosphoinositide metabolism. More detailed analysis demonstrated that NorD reduced the amounts of all in tracellular inositol phosphate isomers, including inositol pentakispho sphate and inositol hexakisphosphate. Vasopressin-stimulated inositol (1,4,5)-trisphosphate accumulation was reduced by 80% and, as a conseq uence, the intracellular calcium mobilization was strongly affected. S imilarly, NorD reduced both the level of inositol (1,4,5)-trisphosphat e and the intracellular free calcium concentration of unstimulated cel ls. NorD blocked phosphoinositide metabolism by reducing the myoinosit ol transporter and, by a consequence, the pool of inositol lipids. Nor D also strongly inhibited WRK(1) cell proliferation with the same EC(5 0) as that observed for the effect on phosphoinositide metabolism. Epi nordidemnin, which was unable to inhibit inositol phosphate accumulati on, had no effect on cell growth. Cyclosporin A, which slightly inhibi ted WRK(1) cell growth, did not significantly affect the calcium-phosp hatidylinositol cascade. Taken together, these results suggest that No rD might interfere with WRK(1) cell growth by inhibiting phosphoinosit ide turnover.