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(The FASEB Journal. 2000;14:1179-1187.)
© 2000 FASEB

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

GIORGIA RAZZINI*,1, CHRISTOPHER P. BERRIE{dagger},1, SARA VIGNATI{ddagger}, MASSIMO BROGGINI{ddagger}, GIUSEPPE MASCETTA§, ANNA BRANCACCIO* and MARCO FALASCA*,§2

* Unit of Physiopathology of Cell Signalling, and
{dagger} Laboratory of Cellular and Molecular Endocrinology, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, via Nazionale, 66030 Santa Maria Imbaro (Chieti), Italy;
{ddagger} Molecular Pharmacology Unit, Istituto di Ricerche Farmacologiche ‘Mario Negri’, via Eritrea, 62, 20157 Milan, Italy; and
§ Laboratory of Molecular Oncology, Fondazione CARIPE, Pescara, Italy

2Correspondence: Unit of Physiopathology of Cell Signalling, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, via Nazionale, 66030 Santa Maria Imbaro (Chieti), Italy. E-mail: falasca{at}cmns.mnegri.it

New efforts in cancer therapy are being focused at various levels of signaling pathways. With phosphoinositide 3-kinase (PI3-K) potentially being necessary for a range of cancer-related functions, we have investigated the influence of selected inositol tris- to hexakisphosphates on cell growth and tumorigenicity. We show that micromolar concentrations of inositol 1,3,4,5,6-pentakisphosphate and inositol 1,4,5,6-tetrakisphosphate [Ins(1,4,5,6)P4] inhibit IGF-1-induced [3H]-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 cancer cell line containing a constitutively active PI3-K. In an ovarian cancer cell line that also contains a constitutively active PI3-K (SKOV-3 cells), Ins(1,4,5,6)P4 again inhibited liquid medium growth. Furthermore, when applied extracellularly, inositol 1,3,4,5-tetrakisphosphate was shown indeed to enter SCLC cells. These effects appeared specifically related to PH domains known to bind to phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P2] and phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], indicating involvement of the PI3-K downstream target protein kinase B (PKB/Akt). This was further supported by inhibition of PKB/Akt PH domain membrane targeting in COS-7 cells by Ins(1,4,5,6)P4. Thus, we propose that specific inositol polyphosphates inhibit PI3-K by competing with PtdIns(3,4,5)P3-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., Mascetta, G., Brancaccio, A., Falasca, M. Novel functional PI 3-kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines.


Key Words: antitumor agents • inositol polyphosphates • PH domain-binding antagonists • phosphatidylinositols




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