Novel functional PI 3-kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines

New efforts in cancer therapy are being focused at various levels of signal ing pathways. With phosphoinositide 3-kinase (PI3-K) potentially being nece ssary for a range of cancer-related functions, we have investigated the inf luence of selected inositol tristo hexakisphosphates on cell growth and tum origenicity. We show that micromolar concentrations of inositol 1,3,4,5,6-p entakisphosphate and inositol 1,4,5,6-tetrakisphosphate [Ins(1,4,5,6)P-4] i nhibit IGF-1-induced [H-3]-thymidine incorporation in human breast cancer ( MCF-7) cells and the ability to grow in liquid medium and form colonies in agarose semisolid medium by small cell lung cancer (SCLC) cells, a human ca ncer cell line containing a constitutively active PI3-K. In an ovarian canc er cell line that also contains a constitutively active PI3-K (SKOV-3 cells ), Ins(1,4,5,6)P-4 again inhibited liquid medium growth. Furthermore, when applied extracellularly, inositol 1,3,4,5-tetrakisphosphate was shown indee d to enter SCLC cells. These effects appeared specifically related to PH do mains known to bind to phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P- 2] and phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4,5)P-3], indicating involvement of the PI3-K downstream target protein kinase B (PKB/Akt). Thi s was further supported by inhibition of PKB/Akt PH domain membrane targeti ng in COS-7 cells by Ins(1,4,5,6)P-4. Thus, we propose that specific inosit ol polyphosphates inhibit PI3-K by competing with PtdIns(3,4,5)P-3-binding PH domains and that this occurs mainly at: the level of the downstream PI3- K target, PKB/Akt.-Razzini, G., Berrie, C. P., Vignati, S., Broggini, M., M ascetta, G., Brancaccio, A., Falasca, M. Novel functional PI3-kinase antago nists inhibit cell growth and tumorigenicity in human cancer cell lines.