Selective inhibition of survival signal transduction pathways enhanced radiosensitivity in human esophageal cancer cell lines in vitro.
OBJECTIVE
The purpose of this study was to examine how selective inhibition of the survival signal transduction pathways affects radiosensitivity in human cancer cell lines.


METHODS
Two human esophageal cancer cell lines, TE-1 (mutant p53) and TE2 (wild-type p53), were used. To inhibit the pathways selectively, 3 specific kinase inhibitors, AG1478 (an inhibitor of EGFR), PD98059 (an inhibitor of MEK) and LY294002 (an inhibitor of PI3K), were combined with radiation.


RESULTS
Radiation in combination with these kinase inhibitors potentiated radiation-induced cell killing synergistically. Enhancement ratios were greater in TE-2 than those in TE-1. Radiation in combination with kinase inhibitors increased the expression of the active form of caspase-3 and the PARP cleavage only in TE-2 that has wild-type p53.


CONCLUSIONS
Targeting the key molecules of the survival signal transduction pathway resulted in potentiation of radiation-induced cell killing. The results of this study suggest that the survival signal transduction pathways would be a molecular target in enhancing radiosensitivity.
Akimoto
Tetsuo
T
Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan. takimoto@showa.gunma-u.ac.jp
Nonaka
Tetsuo
T
Harashima
Koichi
K
Ishikawa
Hitoshi
H
Sakurai
Hideyuki
H
Mitsuhashi
Norio
N
D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D003131:Combined Modality Therapy; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011836:Radiation Tolerance / Q000187:drug effects* / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D011859:Radiography; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D020032:Tyrphostins / Q000494:pharmacology
D061945:Caspase Inhibitors; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D020032:Tyrphostins; C101044:RTKI cpd; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011065:Poly(ADP-ribose) Polymerases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one