Quinoxaline 1,4-dioxides are novel angiogenesis inhibitors that potentiate antitumor effects of ionizing radiation.
We have recently shown that quinoxaline 1,4-dioxides (QdNOs) are potent hypoxia selective cytotoxins that modulate hypoxia inducible factor-1alpha (HIF-1alpha) expression. In this study, we evaluated the cytotoxicity, anti-angiogenic, and radiosensitization activities of the two quinoxaline 1,4-dioxides (QdNOs), BPQ and DCQ. Clonogenic survival, Matrigel, and radiosensitization assays were performed in vitro and in vivo using Lewis lung carcinoma (LLC) and EMT-6 mammary adenocarcinoma cells. Transcript and protein levels of HIF-1alpha and VEGF were determined using RT-PCR and Western blotting, respectively. DCQ showed cytotoxic effects under hypoxic conditions for both cell lines. Treatment with either drug inhibited HIF-1alpha and VEGF secretion, with DCQ being more potent than BPQ. DCQ also inhibited the formation of tube-like structures of ECV-304 endothelial cells in Matrigel by 60-80% and significantly reduced neoangiogenesis in vivo. When combined with radiation (200-1000 cGy), DCQ resulted in the death of 100% of LLC or EMT-6 cells. Using the C57BL/6 mouse model, combined treatment with DCQ and radiation delayed the growth of LLC tumors for 17 days and reduced mean tumor volume by 80% at day 20. However, BPQ combined with radiation did not induce significant tumor regression. Histological analyses revealed a significant increase in tissue necrosis in tumors treated by DCQ and radiation. These results indicate a potent anti-angiogenic and radiation modification effect of two quinoxaline dioxides. These findings should stimulate further research in other tumor models as these compounds could have potential clinical applications in cancer therapy.
Gali-Muhtasib
Hala
H
Department of Biology, American University of Beirut, Beirut, Lebanon. amro@aub.edu.lb
Sidani
Mazen
M
Geara
Fady
F
Mona
Assaf-Diab
AD
Al-Hmaira
Josianne
J
Haddadin
Makhluf J
MJ
Zaatari
Ghazi
G
D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism / Q000532:radiotherapy; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000378:metabolism / Q000532:radiotherapy; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D003131:Combined Modality Therapy; D004338:Drug Combinations; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin / Q000737:chemistry / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000517:prevention & control* / Q000532:radiotherapy; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism; D011810:Quinoxalines / Q000627:therapeutic use*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D011509:Proteoglycans; D011810:Quinoxalines; D011838:Radiation-Sensitizing Agents; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; C003282:quindoxin