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

• Published in: The FASEB journal 2000-06, Vol.14 (9), p.1179-1187
• Main Authors: Razzini, Giorgia, Berrie, Christopher P., Vignati, Sara, Broggini, Massimo, Mascetta, Giuseppe, Brancaccio, Anna, Falasca, Marco
• Format: Article
• Language: English
• Subjects: Animals; antitumor agents; Binding Sites; Cell Division - drug effects; Cell Membrane - enzymology; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; COS Cells; DNA, Neoplasm - biosynthesis; Dose-Response Relationship, Drug; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Humans; Inositol Phosphates - antagonists & inhibitors; Inositol Phosphates - metabolism; Inositol Phosphates - pharmacology; Inositol Phosphates - therapeutic use; inositol polyphosphates; Insulin-Like Growth Factor I - antagonists & inhibitors; Insulin-Like Growth Factor I - pharmacology; Models, Biological; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - metabolism; Neoplasms - pathology; PH domain‐binding antagonists; Phosphatidylinositol 3-Kinases - metabolism; phosphatidylinositols; Phosphoinositide-3 Kinase Inhibitors; Protein Binding - drug effects; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - metabolism; Protein Structure, Tertiary; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Tumor Cells, Cultured
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.14.9.1179

ABSTRACT 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 tristo 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‐tetra‐kisphosphate [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. FASEB J. 14, 1179–1187 (2000)