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

Aim: Cisplatin resistance is an important issue in lung Cancer. We aimed at investigating if the Hedgehog pathway inhibitor GDC-0449 is effective in cisplatin-resistant cells and if it alters intracellular CA(2+)-homeostasis.

Materials and methods: The cytoplasmatic ([CA(2+)](cyto)) and endoplasmatic ([CA(2+)])(ER) CA(2+) concentration of HCC (adeno carcinoma of the lung) and H1339 (small cell lung carcinoma) cells were measured with the calcium indicator dye Fura-2 AM. The expression of the inositol-1,4,5-trisphosphate receptor (IP(3)R) and sarco/endoplasmic reticulum CA(2+)-ATPase (SERCA) were analyzed using western blot analysis.

Results: GDC-0449 inhibited cell growth in cisplatin-naïve and -resistant cells. In both cell types, GDC-0449 increased [CA(2+)](cyto) and reduced endoplasmatic [CA(2+)](ER). Cisplatin failed to considerably alter CA(2+) homeostasis in resistant cells. The effects of GDC-0449 on intracellular CA(2+) homeostasis were not mediated by an altered expression of IP(3)R or SERCA.

Conclusion: GDC-0449 alters intracellular CA(2+) homeostasis and inhibits cell growth in cisplatin-resistant lung Cancer cells.