Abstract 3360: The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca2+-homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells

Abstract

Abstract Cisplatin-resistance is an important issue in lung cancer. The hedgehog signaling pathway (Hh) has been shown to be activated in cancer. GDC-0449 is a low-molecular Hh pathway inhibitor that binds to and inhibits Hh pathway receptor SMO. It is the first systemic SMO-inhibitor that has entered clinical trials. Recently, we could show that GDC-0449 is effective in lung cancer cell lines and that combination with cisplatin gives an additional effect. However, no data on the effect of GDC-0449 on cisplatin-resistant lung cancer cells are available. We aimed at investigating if the hedgehog pathway inhibitor GDC-0449 is effective in cisplatin-resistant cells and if it alters the intracellular Ca2+-homeostasis. The cytoplasmatic ([Ca2+]cyto) and endoplasmatic ([Ca2+]ER) Ca2+-concentration of HCC (adeno carcinoma of the lung) and H1339 (small cell lung carcinoma) cells was measured with the calcium indicator dye Fura-2 AM. The expression of the inositol-1,4,5-trisphosphate receptor (IP3R) and Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) were analyzed using Western Blot analysis. GDC-0449 inhibited cell growth in cisplatin-naïve and -resistant cells. In both cell types, GDC-0449 increased [Ca2+]cyto and reduced endoplasmatic [Ca2+]ER. Cisplatin failed to considerably alter the Ca2+-homeostasis in resistant cells. The effects of GDC-0449 on the intracellular Ca2+-homeostasis were not mediated by an altered expression of IP3R or SERCA. We demonstrate that GDC-0449 alters the intracellular Ca2+-homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3360. doi:1538-7445.AM2012-3360