The antihypertension drug doxazosin inhibits tumor growth and angiogenesis by decreasing VEGFR-2/Akt/mTOR signaling and VEGF and HIF-1α expression
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Mi Sun Park1,2,*, Boh-Ram Kim1,*, Seung Myung Dong1, Seung-Hoon Lee3, Dae-Yong Kim2 and Seung Bae Rho1
1 Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyevonggi-do, Republic of Korea
2 Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, 599, Gwanank-ro, Gwanakgu, Seoul, Republic of Korea
3 Department of Life Science, Yong In University, 470, Samga-dong, Cheoin-gu, Yongin-si Gyeonggi-do, Republic of Korea
* These Authors contributed equally to this work
Seung Bae Rho, email:
Keywords: doxazosin; anti-angiogenic activity; VEGFR-2; Akt/mTOR phosphorylation; endothelial cell
Received: April 29, 2014 Accepted: June 5, 2014 Published: June 6, 2014
Doxazosin is an α1 adrenergic receptor blocker that also exerts antitumor effects. However, the underlying mechanisms by which it modulates PI3K/Akt intracellular signaling are poorly understood. In this study, we reveal that doxazosin functions as a novel antiangiogenic agent by inhibiting vascular endothelial growth factor (VEGF)-induced cell migration and proliferation. It also inhibited VEGF-induced capillary-like structure tube formation in vitro. Doxazosin inhibited the phosphorylation of VEGF receptor-2 (VEGFR-2) and downstream signaling, including PI3K, Akt, 3-phosphoinositide-dependent protein kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and hypoxia-inducible factor 1 (HIF-1α). However, it had no effect on VEGF-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Furthermore, doxazosin reduced tumor growth and suppressed tumor vascularization in a xenograft human ovarian cancer model. These results provide evidence that doxazosin functions in the endothelial cell system to modulate angiogenesis by inhibiting Akt and mTOR phosphorylation and interacting with VEGFR-2.
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