The noni anthraquinone damnacanthal is a multi-kinase inhibitor with potent anti-angiogenic effects.
The natural bioactive compound damnacanthal inhibits several tyrosine kinases. Herein, we show that -in fact- damancanthal is a multi kinase inhibitor. A docking and molecular dynamics simulation approach allows getting further insight on the inhibitory effect of damnacanthal on three different kinases: vascular endothelial growth factor receptor-2, c-Met and focal adhesion kinase. Several of the kinases targeted and inhibited by damnacanthal are involved in angiogenesis. Ex vivo and in vivo experiments clearly demonstrate that, indeed, damnacanthal is a very potent inhibitor of angiogenesis. A number of in vitro assays contribute to determine the specific effects of damnacanthal on each of the steps of the angiogenic process, including inhibition of tubulogenesis, endothelial cell proliferation, survival, migration and production of extracellular matrix remodeling enzyme. Taken altogether, these results suggest that damancanthal could have potential interest for the treatment of cancer and other angiogenesis-dependent diseases.
Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071 Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071 Málaga, Spain.
Javier A
JA
García-Vilas
Department of Chemistry, The City College of New York, New York, USA.
Almudena
A
Pino-Ángeles
Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071 Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071 Málaga, Spain.
Beatriz
B
Martínez-Poveda
Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071 Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071 Málaga, Spain; CIBER de Enfermedades Raras (CIBERER), E-29071 Málaga, Spain.
Ana R
AR
Quesada
Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071 Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071 Málaga, Spain; CIBER de Enfermedades Raras (CIBERER), E-29071 Málaga, Spain. Electronic address: medina@uma.es.
Miguel Ángel
MÁ
Medina
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D015027:Zebrafish / Q000196:embryology
D020533:Angiogenesis Inhibitors; D000880:Anthraquinones; D047428:Protein Kinase Inhibitors; C079170:damnacanthal; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
Angiogenesis; Damnacanthal; Morinda citrifolia; Multi-kinase inhibitor; Noni