Quinoxaline 1,4-dioxides are novel angiogenesis inhibitors that potentiate antitumor effects of ionizing radiation

  • Authors:
    • Hala Gali-Muhtasib
    • Mazen Sidani
    • Fady Geara
    • Assaf-Diab Mona
    • Josianne Al-Hmaira
    • Makhluf J. Haddadin
    • Ghazi Zaatari
  • View Affiliations

  • Published online on: May 1, 2004     https://doi.org/10.3892/ijo.24.5.1121
  • Pages: 1121-1131
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Abstract

We have recently shown that quinoxaline 1,4-dioxides (QdNOs) are potent hypoxia selective cytotoxins that modulate hypoxia inducible factor-1α (HIF-1α) 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-1α 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-1α 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.

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May 2004
Volume 24 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Gali-Muhtasib, H., Sidani, M., Geara, F., Mona, A., Al-Hmaira, J., Haddadin, M.J., & Zaatari, G. (2004). Quinoxaline 1,4-dioxides are novel angiogenesis inhibitors that potentiate antitumor effects of ionizing radiation. International Journal of Oncology, 24, 1121-1131. https://doi.org/10.3892/ijo.24.5.1121
MLA
Gali-Muhtasib, H., Sidani, M., Geara, F., Mona, A., Al-Hmaira, J., Haddadin, M. J., Zaatari, G."Quinoxaline 1,4-dioxides are novel angiogenesis inhibitors that potentiate antitumor effects of ionizing radiation". International Journal of Oncology 24.5 (2004): 1121-1131.
Chicago
Gali-Muhtasib, H., Sidani, M., Geara, F., Mona, A., Al-Hmaira, J., Haddadin, M. J., Zaatari, G."Quinoxaline 1,4-dioxides are novel angiogenesis inhibitors that potentiate antitumor effects of ionizing radiation". International Journal of Oncology 24, no. 5 (2004): 1121-1131. https://doi.org/10.3892/ijo.24.5.1121