Induction of apoptosis by ionizing radiation and CI-1033 in HuCCT-1 cells.
CI-1033 is a quinazoline-based HER family tyrosine kinase inhibitor that is currently being evaluated as a potential anticancer agent. The present study examines the molecular mechanism by which CI-1033 induces apoptosis either as a single agent or in combination with radiation. Although CI-1033 alone did not induce apoptosis, the simultaneous exposure of cells to CI-1033 and radiation induced significant levels of apoptosis. The sequential treatment of cells with CI-1033 followed by radiation induced an even greater effect with 62.6% of cells undergoing apoptosis but this enhanced effect was not seen if cells were treated first with radiation and then CI-1033. The combination treatment induces apoptosis of HuCCT-1 via upregulation of FasL and Bid cleavage. These data suggest that modulation of the Fas-FasL pathway and activation of Bid could be useful for increasing the anti-tumor effect of CI-1033 in this type of cancer.
Murakami
Masateru
M
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biochemical Research, Graduate School of Biochemical Sciences, Hiroshima University, Hiroshima 734-8551, Japan. muramura@hiroshima-u.ac.jp
Sasaki
Tamito
T
Yamasaki
Souichirou
S
Kuwahara
Kenichi
K
Miyata
Hideki
H
Chayama
Kazuaki
K
D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011839:Radiation, Ionizing; D019014:fas Receptor / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009025:Morpholines; D019014:fas Receptor; C420268:Canertinib; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases