Acacetin inhibits in vitro and in vivo angiogenesis and downregulates Stat signaling and VEGF expression.
Angiogenesis is an effective target in cancer control. The antiangiogenic efficacy and associated mechanisms of acacetin, a plant flavone, are poorly known. In the present study, acacetin inhibited growth and survival (up to 92%; P < 0.001), and capillary-like tube formation on Matrigel (up to 98%; P < 0.001) by human umbilical vein endothelial cells (HUVEC) in regular condition, as well as VEGF-induced and tumor cells conditioned medium-stimulated growth conditions. It caused retraction and disintegration of preformed capillary networks (up to 91%; P < 0.001). HUVEC migration and invasion were suppressed by 68% to 100% (P < 0.001). Acacetin inhibited Stat-1 (Tyr701) and Stat-3 (Tyr705) phosphorylation, and downregulated proangiogenic factors including VEGF, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2), and basic fibroblast growth factor (bFGF) in HUVEC. It also suppressed nuclear localization of pStat-3 (Tyr705). Acacetin strongly inhibited capillary sprouting and networking from rat aortic rings and fertilized chicken egg chorioallantoic membrane (CAM; ∼71%; P < 0.001). Furthermore, it suppressed angiogenesis in Matrigel plugs implanted in Swiss albino mice. Acacetin also inhibited tyrosine phosphorylation of Stat-1 and -3, and expression of VEGF in cancer cells. Overall, acacetin inhibits Stat signaling and suppresses angiogenesis in vitro, ex vivo, and in vivo, and therefore, it could be a potential agent to inhibit tumor angiogenesis and growth.
104 Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India. rana_singh@mail.jnu.ac.in.
Tariq A
TA
Bhat
Dhanya
D
Nambiar
Dhanir
D
Tailor
Arttatrana
A
Pal
Rajesh
R
Agarwal
Rana P
RP
Singh
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002196:Capillaries / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology; D047309:Flavones / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011509:Proteoglycans / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D000970:Antineoplastic Agents; D004338:Drug Combinations; D047309:Flavones; D007797:Laminin; D011509:Proteoglycans; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D014443:Tyrosine; D003094:Collagen; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C023717:acacetin