Effects of PKC beta inhibitor enzastaurin on parental and chemoresistant ovarian cancer cell lines

• Published in: Journal of clinical oncology Vol. 24; no. 18_suppl; p. 20037
• Main Authors: Meinhold-Heerlein, I., Bauerschlag, D. O., Bräutigam, K., Maass, N., Mundhenke, C., Hilpert, F., Kaisenberg von, C., Jonat, W., Bauknecht, T., Arnold, N.
• Format: Journal Article
• Language: English
• Published: 20-06-2006
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2006.24.18_suppl.20037

Abstract only
20037
Background: Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase C beta (PKCβ), inhibits induction of angiogenesis and apoptosis. Activation of PKCβ has been correlated with tumor cell proliferation and invasiveness. The impact of Enzastaurin was investigated in an ovarian cancer tissue culture model utilizing the parental cell line HEY and resistant subclones against different cytostatic drugs. Methods: The ovarian cancer cell line HEY was used to develop subclones with selective resistance against Cisplatin, Etoposide, Docetaxel and Paclitaxel, respectively. The ovarian cell line IGROV-1 with high expression of PKC beta served as control. All cell lines were stimulated with 5 μM Enzastaurin for up to four hours. Immunoblotting analyses determined the expression of GSK3β, a target of PKCβ. Proliferation and apoptosis induction after Enzastaurin treatment was analysed by a proliferation assay and DAPI staining. Results: All cell lines showed phosphorylation of GSK3β, the highest expression level was found in parental and Cisplatin-resistant HEY cells as well as in IGROV-1 cells. Phosphorylation decreased after stimulation with 5 μM Enzastaurin for 30 minutes, most obvious detectable in parental and Cisplatin-resistent HEY cells and also IGROV-1 cells. Proliferation and apoptosis assays demonstrated the Paclitaxel- and Docetaxel-resistant HEY cells as the most sensitive cell lines for Enzastaurin treatment. In contrast, Cisplatin-resistant HEY cells and IGROV-1 cells exhibited the highest resistance against Enzastaurin. Conclusion: The results indicate that ovarian cell lines with a high expression level of active PKCβ like Cisplatin-resistant HEY cells and IGROV-1 cells display also strong phosphorylation of GSK3β. Though in these cell lines the inhibitory effect of Enzastaurin is most prominent, the cell proliferation is hardly affected, nor apoptosis is accelerated when Enzastaurin concentrations up to 10–15 μM were used. Compared to the Cisplatin-resistant variants the normal HEY cells are more sensitive to the inhibitor. Taxane-resistant cells seem to respond to low concentrations of Enzastaurin. Therefore, Enzastaurin may become an effectful drug to treat ovarian carcinomas with resistance to Taxane-based chemotherapies.
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