Synchrotron photoactivation of cisplatin elicits an extra number of DNA breaks that stimulate RAD51-mediated repair pathways.
Combination of cis-platinum with ionizing radiation is one of the most promising anticancer treatments that appears to be more efficient than radiotherapy alone. Unlike conventional X-ray emitters, accelerators of high energy particles like synchrotrons display powerful and monochromatizable radiation that makes the induction of an Auger electron cascade in cis-platinum molecules [also called photoactivation of cis-platinum (PAT-Plat)] theoretically possible. Here, we examined the molecular consequences of one of the first attempts of synchrotron PAT-Plat, performed at the European Synchrotron Research Facility (Grenoble-France). PAT-Plat was found to result in an extra number of slowly repairable DNA double-strand breaks, inhibition of DNA-protein kinase activity, dramatic nuclear relocalization of RAD51, hyperphosphorylation of the BRCA1 protein, and activation of proto-oncogenic c-Abl tyrosine kinase.
Corde
Stéphanie
S
Equipe d'Accueil 2941 Rayonnement Synchrotron et Recherche Médicale, Unité IRM, CHU A. Michallon, BP 217, F-38043 Grenoble cedex 09, France.
Balosso
Jacques
J
Elleaume
Hélène
H
Renier
Michel
M
Joubert
Aurélie
A
Biston
Marie-Claude
MC
Adam
Jean-François
JF
Charvet
Anne-Marie
AM
Brochard
Thierry
T
Le Bas
Jean-François
JF
Estève
François
F
Foray
Nicolas
N
D021581:Active Transport, Cell Nucleus; D019313:BRCA1 Protein / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology / Q000528:radiation effects*; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000502:physiology*; D004583:Electrons; D016521:Electrophoresis, Gel, Pulsed-Field; D004789:Enzyme Activation; D005240:Feasibility Studies; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D006258:Head and Neck Neoplasms / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000502:physiology; D009687:Nuclear Proteins; D010777:Photochemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051135:Rad51 Recombinase; D017356:Synchrotrons
D019313:BRCA1 Protein; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016315:Proto-Oncogene Proteins c-abl; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin