Effects of the hedgehog inhibitor GDC-0449, alone or in combination with dasatinib, on BCR-ABL-positive leukemia cells.
Hedgehog (Hh)-glioma-associated oncogene homolog (Gli) signaling is implicated in a large number of human cancers such as leukemia. In this study, we investigated the effects of the potent Hh antagonist GDC-0449 on the BCR-ABL-positive cell line OM9;22 and primary samples when leukemia cells were protected by a feeder cell line (S9 cells). The numbers of OM9;22 cells significantly increased with S9 cells. Treatment of OM9;22 cells with GDC-0449 caused cell growth inhibition and induced apoptosis. Moreover, GDC-0449 inhibited the colony growth of Philadelphia chromosome (Ph)-positive primary samples. We next investigated the effects of a combination of GDC-0449 and dasatinib on these cell lines. The growth inhibition typically promoted by dasatinib was significantly reduced in the presence of S9 cells. Treatment of Ph-positive leukemia cells with GDC-0449 and dasatinib in the presence of S9 caused significantly more cytotoxicity than that caused by each drug alone. Inhibition of Gli1 or Gli2 by siRNA transfection reduced the growth of the Ph-positive cell line K562 and increased cytotoxicity of dasatinib. Moreover, colony formations of Gli1 or Gli2 knockdown cells were also reduced. Data from this study suggest that administration of the Hh inhibitor GDC-0449 inhibits BCR-ABL-positive cell growth and enhances the cytotoxic effects of dasatinib in the presence of feeder cells.
First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan. okabe@tokyo-med.ac.jp
Seiichi
S
Okabe
Tetsuzo
T
Tauchi
Yuko
Y
Tanaka
Seiichiro
S
Katagiri
Kazuma
K
Ohyashiki
D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D061252:Feeder Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
D000813:Anilides; C400551:GLI1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D011725:Pyridines; D011743:Pyrimidines; D034741:RNA, Small Interfering; C509239:SHH protein, human; D013844:Thiazoles; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000069439:Dasatinib