Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways.
Thymoquinone, a component derived from the medial plant Nigella sativa, has been used for medical purposes for more than 2,000 years. Recent studies reported that thymoquinone exhibited inhibitory effects on cell proliferation of many cancer cell lines and hormone-refractory prostate cancer by suppressing androgen receptor and E2F-1. Whether thymoquinone inhibits tumor angiogenesis, the critical step of tumor growth and metastasis, is still unknown. In this study, we found that thymoquinone effectively inhibited human umbilical vein endothelial cell migration, invasion, and tube formation. Thymoquinone inhibited cell proliferation and suppressed the activation of AKT and extracellular signal-regulated kinase. Thymoquinone blocked angiogenesis in vitro and in vivo, prevented tumor angiogenesis in a xenograft human prostate cancer (PC3) model in mouse, and inhibited human prostate tumor growth at low dosage with almost no chemotoxic side effects. Furthermore, we observed that endothelial cells were more sensitive to thymoquinone-induced cell apoptosis, cell proliferation, and migration inhibition compared with PC3 cancer cells. Thymoquinone inhibited vascular endothelial growth factor-induced extracellular signal-regulated kinase activation but showed no inhibitory effects on vascular endothelial growth factor receptor 2 activation. Overall, our results indicate that thymoquinone inhibits tumor angiogenesis and tumor growth and could be used as a potential drug candidate for cancer therapy.
Yi
Tingfang
T
Center for Cancer and Stem Cell Biology, Institute for Bioscience and Technology, Texas A&M University System Health Science Center, 2121 West Holcombe Boulevard, Houston, TX 77030, USA.
Cho
Sung-Gook
SG
Yi
Zhengfang
Z
Pang
Xiufeng
X
Rodriguez
Melissa
M
Wang
Ying
Y
Sethi
Gautam
G
Aggarwal
Bharat B
BB
Liu
Mingyao
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
D016227:Benzoquinones; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C003466:thymoquinone