| Autor: |
Sassi A; UFR Sciences de Santé, Université de Bourgogne, 21000 Dijon, France.; INSERM Research Center U1231-Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France.; Research Unit Bioactive Natural Products and Biotechnology UR17ES49, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia., Fredon M; UFR Sciences de Santé, Université de Bourgogne, 21000 Dijon, France.; INSERM Research Center U1231-Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France., Cotte AK; UFR Sciences de Santé, Université de Bourgogne, 21000 Dijon, France.; INSERM Research Center U1231-Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France., Fuselier C; Faculté des Sciences Exactes et Naturelles, UMR CNRS 7369 MEDyC, Université de Reims Champagne Ardenne, 51687 Reims, France., Schneider C; Faculté des Sciences Exactes et Naturelles, UMR CNRS 7369 MEDyC, Université de Reims Champagne Ardenne, 51687 Reims, France., Martiny L; Faculté des Sciences Exactes et Naturelles, UMR CNRS 7369 MEDyC, Université de Reims Champagne Ardenne, 51687 Reims, France., Monchaud D; UFR Sciences de Santé, Université de Bourgogne, 21000 Dijon, France.; Institut de Chimie Moléculaire (ICMUB), CNRS UMR6302, UBFC, 21078 Dijon, France., Chekir-Ghedira L; Research Unit Bioactive Natural Products and Biotechnology UR17ES49, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia., Aires V; UFR Sciences de Santé, Université de Bourgogne, 21000 Dijon, France.; INSERM Research Center U1231-Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France., Delmas D; UFR Sciences de Santé, Université de Bourgogne, 21000 Dijon, France.; INSERM Research Center U1231-Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France.; Centre de Lutte Contre le Cancer Georges François Leclerc Center, 21000 Dijon, France. |
| Abstrakt: |
Despite the progress made in treatments, melanoma is one of the cancers for which its incidence and mortality have increased during recent decades. In the research of new therapeutic strategies, natural polyphenols such as chrysin could be good candidates owing to their capacities to modulate the different fundamental aspects of tumorigenesis and resistance mechanisms, such as oxidative stress and neoangiogenesis. In the present study, we sought to determine whether chrysin could exert antitumoral effects via the modulation of angiogenesis by acting on oxidative stress and associated DNA damage. For the first time, we show a link between chrysin-induced antiproliferative effects, the activation of the DNA damage pathway, and its ability to limit angiogenesis. More specifically, herein, we show that chrysin induces single- and double-stranded DNA breaks via the activation of the DNA damage response pathway: ATM (ataxia-telangiectasia-mutated)/Chk2 (checkpoint kinase 2) and ATR (ataxia telangiectasia and Rad3-related)/Chk1 (checkpoint kinase 1) pathways. Strong activation of this DNA damage response was found to be partly involved in the ability of chrysin to limit angiogenesis and may partly involve a direct interaction between the polyphenol and DNA G-quadruplex structures responsible for the replication fork collapse. Moreover, these events were associated with a marked reduction in melanoma cells' capacity to secrete proangiogenic factor VEGF-A. The disruption of these key protein actors in tumor growth by chrysin was also confirmed in a syngeneic model of B16 melanoma. This last point is of importance to further consider the use of chrysin as a new therapeutic strategy in melanoma treatment. |
