Radiosensitization by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide under oxia and hypoxia in human colon cancer cells.
BACKGROUND
The sensitizing effects of 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) and ionizing radiation (IR) were determined in four colon cancer cells and in FHs74Int normal intestinal cells.


METHODS
Cell cycle modulation, TUNEL assay, clonogenic survival and DNA damage were examined under oxia or hypoxia. Effects on apoptotic molecules and on p-Akt and Cox-2 protein expression were investigated.


RESULTS
The four cell lines responded differently to DCQ+IR; HT-29 cells were most resistant. Combination treatment caused significant increases in preG1 (apoptosis) in HCT-116, while G2/M arrest occurred in DLD-1. DCQ potentiated IR effects more so under hypoxia than oxia. Pre-exposure of DLD-1 to hypoxia induced 30% apoptosis, and G2/M arrest in oxia. The survival rate was 50% lower in DCQ+IR than DCQ alone and this rate further decreased under hypoxia. FHs74Int normal intestinal cells were more resistant to DCQ+IR than cancer cells.Greater ssDNA damage occurred in DLD-1 exposed to DCQ+IR under hypoxia than oxia. In oxia, p-Akt protein expression increased upon IR exposure and drug pre-treatment inhibited this increase. In contrast, in hypoxia, exposure to IR reduced p-Akt protein and DCQ restored its expression to the untreated control. Apoptosis induced in hypoxic DLD-1 cells was independent of p53-p21 modulation but was associated with an increase in Bax/Bcl-2 ratio and the inhibition of the Cox-2 protein.


CONCLUSIONS
DCQ is a hypoxic cell radiosensitizer in DLD-1 human colon cancer cells.
Itani
Wafica
W
Department of Biology, American University of Beirut, Beirut, Lebanon. wsi02@aub.edu.lb
Geara
Fady
F
Haykal
Joelle
J
Haddadin
Makhluf
M
Gali-Muhtasib
Hala
H
D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology* / Q000532:radiotherapy*; D020552:Comet Assay; D004249:DNA Damage; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D000860:Hypoxia; D020287:In Situ Nick-End Labeling; D007422:Intestines / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology*; D018787:Radiation Oncology / Q000379:methods*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
C490569:2-benzoyl-3-phenyl-6,7-dichloroquinoxaline-1,4-dioxide; D011810:Quinoxalines; D011838:Radiation-Sensitizing Agents; D010100:Oxygen