title: BJ-1108, a 6-Amino-2,4,5-Trimethylpyridin-3-ol Analog, Inhibits Serotonin-Induced Angiogenesis and Tumor Growth through PI3K/NOX Pathway.
abstract: 5-Hydroxytryptamine (5-HT) induces proliferation of cancer cells and vascular cells. In addition to 5-HT production by several cancer cells including gastrointestinal and breast cancer, a significant level of 5-HT is released from activated platelets in the thrombotic environment of tumors, suggesting that inhibition of 5-HT signaling may constitute a new target for antiangiogenic anticancer drug discovery. In the current study we clearly demonstrate that 5-HT-induced angiogenesis was mediated through the 5-HT1 receptor-linked Gβγ/Src/PI3K pathway, but not through the MAPK/ERK/p38 pathway. In addition, 5-HT induced production of NADPH oxidase (NOX)-derived reactive oxygen species (ROS). In an effort to develop new molecularly targeted anticancer agents against 5-HT action in tumor growth, we demonstrate that BJ-1108, a derivative of 6-amino-2,4,5-trimethylpyridin-3-ol, significantly inhibited 5-HT-induced angiogenesis. In addition, BJ-1108 induced a significant reduction in the size and weight of excised tumors in breast cancer cell-inoculated CAM assay, showing proportionate suppression of tumor growth along with inhibition of angiogenesis. In human umbilical vein endothelial cells (HUVECs), BJ-1108 significantly suppressed 5-HT-induced ROS generation and phosphorylation of PI3K/Akt but not of Src. Unlike NOX inhibitors, BJ-1108, which showed better antioxidant activity than vitamin C, barely suppressed superoxide anion induced by mevalonate or geranylgeranyl pyrophosphate which directly activates NOX without help from other signaling molecules in HUVECs, implying that the anti-angiogenic action of BJ-1108 was not mediated through direct action on NOX activation, or free radical scavenging activity. In conclusion, BJ-1108 inhibited 5-HT-induced angiogenesis through PI3K/NOX signaling but not through Src, ERK, or p38.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Suhrid
authors.initials: S
authors.lastname: Banskota
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Jaya
authors.initials: J
authors.lastname: Gautam
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Sushil C
authors.initials: SC
authors.lastname: Regmi
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Gurung
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Myo-Hyeon
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Seung Joo
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Tae-Gyu
authors.initials: TG
authors.lastname: Nam
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Byeong-Seon
authors.initials: BS
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1 / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D000814:Aniline Compounds; D044387:GTP-Binding Protein beta Subunits; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases; C000609005:BJ-1108
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