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


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.


CONCLUSIONS
GDC-0449 alters intracellular Ca(2+) homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells.
Division of Respiratory Medicine, Medical Clinic, Ziemssenstr. 1, 80336 Munich, Germany.
Fei
F
Tian
Kathrin
K
Schrödl
Rosemarie
R
Kiefl
Rudolf Maria
RM
Huber
Albrecht
A
Bergner
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000813:Anilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D016257:Fura-2; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D000813:Anilides; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C538724:HhAntag691; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011725:Pyridines; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002945:Cisplatin; D002118:Calcium; D016257:Fura-2